diff --git a/colcon_core/task/python/build.py b/colcon_core/task/python/build.py
index a72c1a54e..5320a939c 100644
--- a/colcon_core/task/python/build.py
+++ b/colcon_core/task/python/build.py
@@ -70,6 +70,7 @@ async def build(self, *, additional_hooks=None):  # noqa: D102
             Path(__file__).parent / 'template' / 'sitecustomize.py.em',
             prefix_override / 'sitecustomize.py',
             {
+                'current_prefix': sys.prefix,
                 'site_prefix': args.install_base,
             })
 
diff --git a/colcon_core/task/python/template/sitecustomize.py.em b/colcon_core/task/python/template/sitecustomize.py.em
index 5ed6f35ef..b6bbe2f03 100644
--- a/colcon_core/task/python/template/sitecustomize.py.em
+++ b/colcon_core/task/python/template/sitecustomize.py.em
@@ -1,3 +1,4 @@
 import sys
-sys.real_prefix = sys.prefix
-sys.prefix = sys.exec_prefix = @repr(site_prefix)
+if sys.prefix == @repr(current_prefix):
+    sys.real_prefix = sys.prefix
+    sys.prefix = sys.exec_prefix = @repr(site_prefix)