diff --git a/mypyc/irbuild/specialize.py b/mypyc/irbuild/specialize.py
index 29820787d10c..2e92c05802e0 100644
--- a/mypyc/irbuild/specialize.py
+++ b/mypyc/irbuild/specialize.py
@@ -14,7 +14,7 @@
 
 from __future__ import annotations
 
-from typing import Callable, Final, Optional
+from typing import Callable, Final, Optional, cast
 
 from mypy.nodes import (
     ARG_NAMED,
@@ -40,6 +40,7 @@
     Call,
     Extend,
     Integer,
+    PrimitiveDescription,
     RaiseStandardError,
     Register,
     Truncate,
@@ -587,26 +588,81 @@ def translate_isinstance(builder: IRBuilder, expr: CallExpr, callee: RefExpr) ->
     if not (len(expr.args) == 2 and expr.arg_kinds == [ARG_POS, ARG_POS]):
         return None
 
-    if isinstance(expr.args[1], (RefExpr, TupleExpr)):
-        builder.types[expr.args[0]] = AnyType(TypeOfAny.from_error)
+    obj_expr = expr.args[0]
+    type_expr = expr.args[1]
 
-        irs = builder.flatten_classes(expr.args[1])
+    if isinstance(type_expr, TupleExpr) and not type_expr.items:
+        # we can compile this case to a noop
+        return builder.false()
+
+    if isinstance(type_expr, (RefExpr, TupleExpr)):
+        builder.types[obj_expr] = AnyType(TypeOfAny.from_error)
+
+        irs = builder.flatten_classes(type_expr)
         if irs is not None:
             can_borrow = all(
                 ir.is_ext_class and not ir.inherits_python and not ir.allow_interpreted_subclasses
                 for ir in irs
             )
-            obj = builder.accept(expr.args[0], can_borrow=can_borrow)
+            obj = builder.accept(obj_expr, can_borrow=can_borrow)
             return builder.builder.isinstance_helper(obj, irs, expr.line)
 
-    if isinstance(expr.args[1], RefExpr):
-        node = expr.args[1].node
+    if isinstance(type_expr, RefExpr):
+        node = type_expr.node
         if node:
             desc = isinstance_primitives.get(node.fullname)
             if desc:
-                obj = builder.accept(expr.args[0])
+                obj = builder.accept(obj_expr)
                 return builder.primitive_op(desc, [obj], expr.line)
 
+    elif isinstance(type_expr, TupleExpr):
+        node_names: list[str] = []
+        for item in type_expr.items:
+            if not isinstance(item, RefExpr):
+                return None
+            if item.node is None:
+                return None
+            if item.node.fullname not in node_names:
+                node_names.append(item.node.fullname)
+
+        descs = [isinstance_primitives.get(fullname) for fullname in node_names]
+        if None in descs:
+            # not all types are primitive types, abort
+            return None
+
+        obj = builder.accept(obj_expr)
+
+        retval = Register(bool_rprimitive)
+        pass_block = BasicBlock()
+        fail_block = BasicBlock()
+        exit_block = BasicBlock()
+
+        # Chain the checks: if any succeed, jump to pass_block; else, continue
+        for i, desc in enumerate(descs):
+            is_last = i == len(descs) - 1
+            next_block = fail_block if is_last else BasicBlock()
+            builder.add_bool_branch(
+                builder.primitive_op(cast(PrimitiveDescription, desc), [obj], expr.line),
+                pass_block,
+                next_block,
+            )
+            if not is_last:
+                builder.activate_block(next_block)
+
+        # If any check passed
+        builder.activate_block(pass_block)
+        builder.assign(retval, builder.true(), expr.line)
+        builder.goto(exit_block)
+
+        # If all checks failed
+        builder.activate_block(fail_block)
+        builder.assign(retval, builder.false(), expr.line)
+        builder.goto(exit_block)
+
+        # Return the result
+        builder.activate_block(exit_block)
+        return retval
+
     return None
 
 
diff --git a/mypyc/test-data/irbuild-isinstance.test b/mypyc/test-data/irbuild-isinstance.test
index 0df9448b819f..36a9300350bd 100644
--- a/mypyc/test-data/irbuild-isinstance.test
+++ b/mypyc/test-data/irbuild-isinstance.test
@@ -189,3 +189,31 @@ def is_tuple(x):
 L0:
     r0 = PyTuple_Check(x)
     return r0
+
+[case testTupleOfPrimitives]
+from typing import Any
+
+def is_instance(x: Any) -> bool:
+    return isinstance(x, (str, int, bytes))
+
+[out]
+def is_instance(x):
+    x :: object
+    r0, r1, r2 :: bit
+    r3 :: bool
+L0:
+    r0 = PyUnicode_Check(x)
+    if r0 goto L3 else goto L1 :: bool
+L1:
+    r1 = PyLong_Check(x)
+    if r1 goto L3 else goto L2 :: bool
+L2:
+    r2 = PyBytes_Check(x)
+    if r2 goto L3 else goto L4 :: bool
+L3:
+    r3 = 1
+    goto L5
+L4:
+    r3 = 0
+L5:
+    return r3
diff --git a/mypyc/test-data/run-misc.test b/mypyc/test-data/run-misc.test
index 129946a4c330..1074906357ee 100644
--- a/mypyc/test-data/run-misc.test
+++ b/mypyc/test-data/run-misc.test
@@ -1173,3 +1173,26 @@ def test_dummy_context() -> None:
     with c:
         assert c.c == 1
     assert c.c == 0
+
+[case testIsInstanceTuple]
+from typing import Any
+
+def isinstance_empty(x: Any) -> bool:
+    return isinstance(x, ())
+def isinstance_single(x: Any) -> bool:
+    return isinstance(x, (str,))
+def isinstance_multi(x: Any) -> bool:
+    return isinstance(x, (str, int))
+
+def test_isinstance_empty() -> None:
+    assert isinstance_empty("a") is False
+    assert isinstance_empty(1) is False
+    assert isinstance_empty(None) is False
+def test_isinstance_single() -> None:
+    assert isinstance_single("a") is True
+    assert isinstance_single(1) is False
+    assert isinstance_single(None) is False
+def test_isinstance_multi() -> None:
+    assert isinstance_multi("a") is True
+    assert isinstance_multi(1) is True
+    assert isinstance_multi(None) is False