diff --git a/src/memray/commands/run.py b/src/memray/commands/run.py
index 2808ade..8b750c7 100644
--- a/src/memray/commands/run.py
+++ b/src/memray/commands/run.py
@@ -51,17 +51,26 @@ def _run_tracker(
     with tracker:
         pid = os.getpid()
         try:
+            # Check if isolation flags are active (e.g., -I or -P).
+            # When these are used, Python suppresses its own sys.path
+            # manipulations, so we should avoid overwriting sys.path[0]
+            # to prevent conflicting with the interpreter's intentions.
+            isolation_flags_active = sys.flags.isolated
+
             if args.run_as_module:
-                sys.path[0] = os.getcwd()
+                if not isolation_flags_active:
+                    sys.path[0] = os.getcwd()
                 # run_module will replace argv[0] with the script's path
                 sys.argv = ["", *args.script_args]
                 runpy.run_module(args.script, run_name="__main__", alter_sys=True)
             elif args.run_as_cmd:
-                sys.path[0] = ""
+                if not isolation_flags_active:
+                    sys.path[0] = ""
                 sys.argv = ["-c", *args.script_args]
                 exec(args.script, {"__name__": "__main__"})
             else:
-                sys.path[0] = str(pathlib.Path(args.script).resolve().parent.absolute())
+                if not isolation_flags_active:
+                    sys.path[0] = str(pathlib.Path(args.script).resolve().parent.absolute())
                 sys.argv = [args.script, *args.script_args]
                 runpy.run_path(args.script, run_name="__main__")
         finally: