diff --git a/htslib/synced_bcf_reader.h b/htslib/synced_bcf_reader.h
index a81ac371d..e0455501c 100644
--- a/htslib/synced_bcf_reader.h
+++ b/htslib/synced_bcf_reader.h
@@ -99,7 +99,8 @@ typedef enum
     BCF_SR_PAIR_LOGIC,          // combination of the PAIR_* values above
     BCF_SR_ALLOW_NO_IDX,        // allow to proceed even if required index is not present (at the user's risk)
     BCF_SR_REGIONS_OVERLAP,     // include overlapping records with POS outside the regions: 0=no, 1=VCF line overlap, 2=true variant overlap [1]
-    BCF_SR_TARGETS_OVERLAP      // include overlapping records with POS outside the targets: 0=no, 1=VCF line overlap, 2=true variant overlap [0]
+    BCF_SR_TARGETS_OVERLAP,     // include overlapping records with POS outside the targets: 0=no, 1=VCF line overlap, 2=true variant overlap [0]
+    BCF_SR_AUTO_TARGETS_FROM_REGIONS    // route a dense single-base regions file through the streaming-targets code path; sets readers->targets, so incompatible with bcf_sr_set_targets() [off]
 }
 bcf_sr_opt_t;
 
diff --git a/synced_bcf_reader.c b/synced_bcf_reader.c
index 7769132fa..e2df73556 100644
--- a/synced_bcf_reader.c
+++ b/synced_bcf_reader.c
@@ -39,6 +39,7 @@ DEALINGS IN THE SOFTWARE.  */
 #include "htslib/kseq.h"
 #include "htslib/khash_str2int.h"
 #include "htslib/bgzf.h"
+#include "htslib/hfile.h"
 #include "htslib/thread_pool.h"
 #include "bcf_sr_sort.h"
 
@@ -70,6 +71,7 @@ typedef struct
     sr_sort_t sort;
     int regions_overlap, targets_overlap;
     int *closefile;             // close htsfile with sync reader close or not
+    int auto_targets_from_regions;  // BCF_SR_AUTO_TARGETS_FROM_REGIONS opt-in
 }
 aux_t;
 
@@ -141,6 +143,10 @@ int bcf_sr_set_opt(bcf_srs_t *readers, bcf_sr_opt_t opt, ...)
             if ( readers->targets ) readers->targets->overlap = BCF_SR_AUX(readers)->targets_overlap;
             return 0;
 
+        case BCF_SR_AUTO_TARGETS_FROM_REGIONS:
+            BCF_SR_AUX(readers)->auto_targets_from_regions = 1;
+            return 0;
+
         default:
             break;
     }
@@ -187,6 +193,88 @@ static int *init_filters(bcf_hdr_t *hdr, const char *filters, int *nfilters)
     return NULL;
 }
 
+// Sniff a regions BED/TSV: returns 1 iff (a) the path is a regular local
+// file we can safely re-open, (b) the first SNIFF_LINES non-comment entries
+// are *all* single-base regions (CHROM\tN-1\tN), and (c) those entries are
+// densely packed (average intra-chromosome inter-entry distance below
+// DENSITY_BP). Used by bcf_sr_set_regions() when the caller has opted in
+// via BCF_SR_AUTO_TARGETS_FROM_REGIONS to auto-promote dense single-base
+// BEDs to the streaming-targets path (samtools/bcftools#2557): the default
+// per-region `tbx_itr_queryi()` path is 300-500x slower than a sequential
+// scan at SNP-panel sizes (84M entries / 23GB VCF didn't complete in 11+
+// hours of 100% CPU in production).
+//
+// The density check rejects sparse BEDs (e.g. ~11 SNPs per chromosome)
+// where streaming would do a full-chromosome scan to satisfy a handful of
+// records — pre-promotion the tabix seek path is the cheap one there.
+#define BCF_SR_REGIONS_SNIFF_LINES 256
+#define BCF_SR_REGIONS_DENSITY_BP  10000
+static int sniff_regions_singlebase(const char *fname)
+{
+    // Bail on inputs whose bytes are gone after the sniff close: FIFOs,
+    // stdin, character devices.  Each subsequent hts_open() in
+    // bcf_sr_regions_init() would see a truncated stream (or block) for
+    // these.  Remote URLs reopen freshly per hts_open() and are safe in
+    // principle, but the extra round-trip outweighs the heuristic value
+    // here — keep the auto-promote local-files-only.
+    if ( hisremote(fname) ) return 0;
+    if ( fname[0]=='-' && fname[1]==0 ) return 0;
+    struct stat sb;
+    if ( stat(fname, &sb) != 0 ) return 0;
+    if ( !S_ISREG(sb.st_mode) ) return 0;
+
+    htsFile *fp = hts_open(fname, "r");
+    if (!fp) return 0;
+    kstring_t line = {0,0,0};
+    kstring_t prev_chr = {0,0,0};
+    hts_pos_t prev_pos = -1;
+    hts_pos_t total_intra_dist = 0;
+    int n = 0, n_intra = 0, all_singlebase = 1;
+    while (n < BCF_SR_REGIONS_SNIFF_LINES)
+    {
+        int ret = hts_getline(fp, KS_SEP_LINE, &line);
+        if (ret < 0) break;     // EOF or read error
+        if (line.l == 0 || line.s[0] == '#') continue;  // skip headers/comments
+        // Parse CHROM\tSTART\tEND[\t...]. BED 1-bp regions have END-START==1.
+        char *chr = line.s;
+        char *p = line.s;
+        while (*p && *p != '\t') p++;
+        if (*p != '\t') { all_singlebase = 0; break; }
+        size_t chr_len = p - chr;
+        char *start_s = ++p;
+        while (*p && *p != '\t') p++;
+        if (*p != '\t') { all_singlebase = 0; break; }
+        char *end_s = ++p;
+        hts_pos_t start = strtoll(start_s, NULL, 10);
+        hts_pos_t end   = strtoll(end_s,   NULL, 10);
+        if (end - start != 1) { all_singlebase = 0; break; }
+
+        if ( prev_chr.l == chr_len && prev_pos >= 0 &&
+             memcmp(prev_chr.s, chr, chr_len) == 0 )
+        {
+            hts_pos_t d = start - prev_pos;
+            if (d < 0) d = -d;
+            total_intra_dist += d;
+            n_intra++;
+        }
+        prev_chr.l = 0;
+        kputsn(chr, chr_len, &prev_chr);
+        prev_pos = start;
+        n++;
+    }
+    free(line.s);
+    free(prev_chr.s);
+    if (hts_close(fp) < 0)
+        hts_log_error("Error on closing %s", fname);
+    if ( !all_singlebase || n != BCF_SR_REGIONS_SNIFF_LINES ) return 0;
+    // Need at least one same-chrom comparison and the sample must be dense.
+    // (If every entry sits on a different chromosome, the panel is sparse
+    // by construction — reject.)
+    if ( n_intra == 0 ) return 0;
+    if ( total_intra_dist / n_intra > BCF_SR_REGIONS_DENSITY_BP ) return 0;
+    return 1;
+}
+
 int bcf_sr_set_regions(bcf_srs_t *readers, const char *regions, int is_file)
 {
     if ( readers->nreaders || readers->regions )
@@ -197,6 +285,24 @@ int bcf_sr_set_regions(bcf_srs_t *readers, const char *regions, int is_file)
         return 0;
     }
 
+    // #2557 fastpath: a dense single-base BED (typical SNP panel: HGDP+1kGP
+    // 84M sites, AADR 1240k, PGS Catalog) hits a 300-500x per-region seek
+    // overhead in the default path. The streaming-targets code path
+    // (bcf_sr_set_targets) handles the same workload at near-baseline
+    // speed. Opt-in via BCF_SR_AUTO_TARGETS_FROM_REGIONS — when set, the
+    // sniffer decides whether the file qualifies. The opt-in is required
+    // because this routes regions through readers->targets, which is
+    // observable to callers and incompatible with a subsequent
+    // bcf_sr_set_targets() call.  The 0/1/2 --regions-overlap semantics
+    // match --targets-overlap so the user-set value carries over unchanged.
+    if ( is_file
+         && BCF_SR_AUX(readers)->auto_targets_from_regions
+         && sniff_regions_singlebase(regions) )
+    {
+        BCF_SR_AUX(readers)->targets_overlap = BCF_SR_AUX(readers)->regions_overlap;
+        return bcf_sr_set_targets(readers, regions, is_file, 0);
+    }
+
     readers->regions = bcf_sr_regions_init(regions,is_file,0,1,-2);
     if ( !readers->regions ) return -1;
     readers->explicit_regs = 1;
diff --git a/test/bcf-sr/regions-fastpath.bed b/test/bcf-sr/regions-fastpath.bed
new file mode 100644
index 000000000..628e24d4c
--- /dev/null
+++ b/test/bcf-sr/regions-fastpath.bed
@@ -0,0 +1,300 @@
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diff --git a/test/bcf-sr/regions-fastpath.vcf b/test/bcf-sr/regions-fastpath.vcf
new file mode 100644
index 000000000..39f2b044a
--- /dev/null
+++ b/test/bcf-sr/regions-fastpath.vcf
@@ -0,0 +1,606 @@
+##fileformat=VCFv4.2
+##contig=<ID=1,length=100000>
+##contig=<ID=2,length=100000>
+##contig=<ID=3,length=100000>
+##FORMAT=<ID=GT,Number=1,Type=String,Description="Genotype">
+#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO	FORMAT	S1
+1	100	.	A	G	100	PASS	.	GT	0/1
+1	150	.	A	G	100	PASS	.	GT	0/1
+1	200	.	A	G	100	PASS	.	GT	0/1
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+1	600	.	A	G	100	PASS	.	GT	0/1
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+1	800	.	A	G	100	PASS	.	GT	0/1
+1	850	.	A	G	100	PASS	.	GT	0/1
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+3	5000	.	A	G	100	PASS	.	GT	0/1
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+3	6000	.	A	G	100	PASS	.	GT	0/1
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+3	8000	.	A	G	100	PASS	.	GT	0/1
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+3	9200	.	A	G	100	PASS	.	GT	0/1
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+3	9300	.	A	G	100	PASS	.	GT	0/1
+3	9350	.	A	G	100	PASS	.	GT	0/1
+3	9400	.	A	G	100	PASS	.	GT	0/1
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+3	9500	.	A	G	100	PASS	.	GT	0/1
+3	9550	.	A	G	100	PASS	.	GT	0/1
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+3	9700	.	A	G	100	PASS	.	GT	0/1
+3	9750	.	A	G	100	PASS	.	GT	0/1
+3	9800	.	A	G	100	PASS	.	GT	0/1
+3	9850	.	A	G	100	PASS	.	GT	0/1
+3	9900	.	A	G	100	PASS	.	GT	0/1
+3	9950	.	A	G	100	PASS	.	GT	0/1
+3	10000	.	A	G	100	PASS	.	GT	0/1
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diff --git a/test/test-bcf-sr.c b/test/test-bcf-sr.c
index 1cd198fa0..94fb18dc1 100644
--- a/test/test-bcf-sr.c
+++ b/test/test-bcf-sr.c
@@ -62,8 +62,12 @@ void HTS_NORETURN usage(int exit_code)
     fprintf(stderr, "   -O, --output-fmt <fmt>       fmt: vcf,bcf,summary\n");
     fprintf(stderr, "   -p, --pair <logic[+ref]>     logic: snps,indels,both,snps+ref,indels+ref,both+ref,exact,some,all\n");
     fprintf(stderr, "   -r, --regions <reg_list>     comma-separated list of regions\n");
+    fprintf(stderr, "   -R, --regions-file <file>    BED/tab file of regions (exercises bcf_sr_set_regions is_file=1)\n");
     fprintf(stderr, "   -t, --targets <reg_list>     comma-separated list of targets\n");
+    fprintf(stderr, "   -T, --targets-file <file>    file of targets (exercises bcf_sr_set_targets is_file=1)\n");
     fprintf(stderr, "   -u, --usefptr                use hfile pointer interface on reader addition\n");
+    fprintf(stderr, "       --auto-targets-from-regions\n");
+    fprintf(stderr, "                                set BCF_SR_AUTO_TARGETS_FROM_REGIONS (sniff-and-promote -R)\n");
     fprintf(stderr, "\n");
     exit(exit_code);
 }
@@ -131,18 +135,23 @@ int main(int argc, char *argv[])
         {"output-fmt",required_argument,NULL,'O'},
         {"pair",required_argument,NULL,'p'},
         {"regions",required_argument,NULL,'r'},
+        {"regions-file",required_argument,NULL,'R'},
         {"targets",required_argument,NULL,'t'},
+        {"targets-file",required_argument,NULL,'T'},
         {"no-index",no_argument,NULL,1000},
         {"args",no_argument,NULL,1001},
+        {"auto-targets-from-regions",no_argument,NULL,1002},
         {"usefptr",no_argument,NULL,'u'},
         {NULL,0,NULL,0}
     };
 
     int c, pair = 0, use_index = 1, use_fofn = 1, usefptr = 0;
+    int auto_targets_from_regions = 0;
     enum htsExactFormat out_fmt = text_format; // for original pos + alleles
     const char *out_fn = NULL, *regions = NULL, *targets = NULL;
+    int regions_is_file = 0, targets_is_file = 0;
     htsFile **htsfp = NULL;
-    while ((c = getopt_long(argc, argv, "o:O:p:r:t:hu", loptions, NULL)) >= 0)
+    while ((c = getopt_long(argc, argv, "o:O:p:r:R:t:T:hu", loptions, NULL)) >= 0)
     {
         switch (c)
         {
@@ -173,15 +182,26 @@ int main(int argc, char *argv[])
             case 'r':
                 regions = optarg;
                 break;
+            case 'R':
+                regions = optarg;
+                regions_is_file = 1;
+                break;
             case 't':
                 targets = optarg;
                 break;
+            case 'T':
+                targets = optarg;
+                targets_is_file = 1;
+                break;
             case 1000:
                 use_index = 0;
                 break;
             case 1001:
                 use_fofn = 0;
                 break;
+            case 1002:
+                auto_targets_from_regions = 1;
+                break;
             case 'u':
                 usefptr = 1;    //use htsfile interface instead of fname i/f
                 break;
@@ -211,16 +231,19 @@ int main(int argc, char *argv[])
     } else {
         bcf_sr_set_opt(sr, BCF_SR_ALLOW_NO_IDX);
     }
+    if (auto_targets_from_regions) {
+        bcf_sr_set_opt(sr, BCF_SR_AUTO_TARGETS_FROM_REGIONS);
+    }
 
     if (regions)
     {
-        if (bcf_sr_set_regions(sr, regions, 0) != 0)
+        if (bcf_sr_set_regions(sr, regions, regions_is_file) != 0)
             error("Failed to set regions\n");
     }
 
     if (targets)
     {
-        if (bcf_sr_set_targets(sr, targets, 0, 0) != 0)
+        if (bcf_sr_set_targets(sr, targets, targets_is_file, 0) != 0)
             error("Failed to set targets\n");
     }
 
diff --git a/test/test.pl b/test/test.pl
index eaa65ea30..358febd4f 100755
--- a/test/test.pl
+++ b/test/test.pl
@@ -59,6 +59,7 @@
 run_test('test_bcf_sr_no_index',$opts);
 run_test('test_bcf_sr_range', $opts);
 run_test('test_bcf_sr_hreader', $opts);
+run_test('test_bcf_sr_regions_fastpath', $opts);
 run_test('test_command',$opts,cmd=>'test-bcf-translate -',out=>'test-bcf-translate.out');
 run_test('test_convert_padded_header',$opts);
 run_test('test_rebgzip',$opts);
@@ -1425,6 +1426,51 @@ sub test_bcf_sr_hreader {
     passed($opts, $test);
 }
 
+sub test_bcf_sr_regions_fastpath {
+    # Regression test for samtools/bcftools#2557. With
+    # BCF_SR_AUTO_TARGETS_FROM_REGIONS set, bcf_sr_set_regions(file=1) sniffs
+    # the BED and routes dense single-base panels through the streaming-
+    # targets path. The fixture has 300 entries on 3 contigs spaced ~100bp
+    # apart, so it clears the sniffer's count and density gates.
+    #
+    # Three runs over the same fixture, all required to match:
+    #   - slow path:   -R FILE                          (per-region tbx_itr_queryi)
+    #   - fastpath:    -R FILE + auto-targets opt       (sniff + set_targets)
+    #   - -T control:  -T FILE                          (set_targets directly)
+    # Slow path and fastpath take genuinely different code paths inside
+    # bcf_sr_next_line(), so a regression in either is visible in their diff
+    # (avoids the prior tautology where -R-fastpath literally re-invoked
+    # set_targets).  The -T diff additionally pins regions/targets parity.
+    my ($opts, %args) = @_;
+    my $test = "test_bcf_sr_regions_fastpath";
+    my $vcfdir = "$$opts{path}/bcf-sr";
+    print "$test:\n";
+
+    # bgzip + tabix-index the fixture BED and VCF in the tmp dir.
+    foreach my $base ('regions-fastpath.bed', 'regions-fastpath.vcf') {
+        my $preset = ($base =~ /\.bed$/) ? 'bed' : 'vcf';
+        my ($ret) = _cmd("cp $vcfdir/$base $$opts{tmp}/ && $$opts{bin}/bgzip -f $$opts{tmp}/$base && $$opts{bin}/tabix -p $preset $$opts{tmp}/$base.gz");
+        if ($ret) { failed($opts, $test, "Failed to prepare fixture $base"); return; }
+    }
+    my $vcf = "$$opts{tmp}/regions-fastpath.vcf.gz";
+    my $bed = "$$opts{tmp}/regions-fastpath.bed.gz";
+
+    my $out_slow = "$$opts{tmp}/regions-fastpath.slow.out.vcf";
+    my $out_fast = "$$opts{tmp}/regions-fastpath.fast.out.vcf";
+    my $out_T    = "$$opts{tmp}/regions-fastpath.T.out.vcf";
+    my ($r1) = _cmd("$$opts{path}/test-bcf-sr -O vcf -o $out_slow -R $bed --args $vcf");
+    if ($r1) { failed($opts, $test, "test-bcf-sr -R (slow path) failed"); return; }
+    my ($r2) = _cmd("$$opts{path}/test-bcf-sr -O vcf -o $out_fast --auto-targets-from-regions -R $bed --args $vcf");
+    if ($r2) { failed($opts, $test, "test-bcf-sr -R (fastpath) failed"); return; }
+    my ($r3) = _cmd("$$opts{path}/test-bcf-sr -O vcf -o $out_T -T $bed --args $vcf");
+    if ($r3) { failed($opts, $test, "test-bcf-sr -T (control) failed"); return; }
+    my ($r4) = _cmd("diff $out_slow $out_fast");
+    if ($r4) { failed($opts, $test, "fastpath output differs from slow path"); return; }
+    my ($r5) = _cmd("diff $out_slow $out_T");
+    if ($r5) { failed($opts, $test, "slow-path output differs from -T control"); return; }
+    passed($opts, $test);
+}
+
 sub test_command
 {
     my ($opts, %args) = @_;