diff --git a/Lib/profiling/sampling/sample.py b/Lib/profiling/sampling/sample.py
index 6a76bbeeb24ee3..9195f5ee6dd390 100644
--- a/Lib/profiling/sampling/sample.py
+++ b/Lib/profiling/sampling/sample.py
@@ -58,6 +58,10 @@ def __init__(self, pid, sample_interval_usec, all_threads, *, mode=PROFILING_MOD
         try:
             self.unwinder = self._new_unwinder(native, gc, opcodes, skip_non_matching_threads)
         except RuntimeError as err:
+            if os.name == "nt" and sys.executable.endswith("python.exe"):
+                raise SystemExit(
+                    "Running profiling.sampling from virtualenv on Windows platform is not supported"
+                ) from err
             raise SystemExit(err) from err
         # Track sample intervals and total sample count
         self.sample_intervals = deque(maxlen=100)