diff --git a/pkgs/development/python-modules/pypdfium2/default.nix b/pkgs/development/python-modules/pypdfium2/default.nix
index 933302eb81e3..66cdf166a6fb 100644
--- a/pkgs/development/python-modules/pypdfium2/default.nix
+++ b/pkgs/development/python-modules/pypdfium2/default.nix
@@ -1,4 +1,5 @@
 {
+  stdenv,
   lib,
   pkgs,
   buildPythonPackage,
@@ -9,6 +10,9 @@
   numpy,
   pillow,
   pytestCheckHook,
+  removeReferencesTo,
+  python,
+  replaceVars,
 }:
 
 let
@@ -37,6 +41,12 @@ let
       hash = "sha256-3JA7cW/xaEj/DxMHEypROwrKGo7EwUEcipRqALTvydw=";
     };
 
+    patches = [
+      (replaceVars ./fix-cc-detection.patch {
+        cc = "${stdenv.cc.targetPrefix}cc";
+      })
+    ];
+
     build-system = [
       setuptools-scm
     ];
@@ -62,6 +72,10 @@ buildPythonPackage rec {
     setuptools-scm
   ];
 
+  nativeBuildInputs = [
+    removeReferencesTo
+  ];
+
   propagatedBuildInputs = [
     pdfium-binaries
   ];
@@ -104,6 +118,11 @@ buildPythonPackage rec {
     '';
   env.PDFIUM_PLATFORM = "system:${pdfiumVersion}";
 
+  # Remove references to stdenv in comments.
+  postInstall = ''
+    remove-references-to -t ${stdenv.cc.cc} $out/${python.sitePackages}/pypdfium2_raw/bindings.py
+  '';
+
   nativeCheckInputs = [
     numpy
     pillow
diff --git a/pkgs/development/python-modules/pypdfium2/fix-cc-detection.patch b/pkgs/development/python-modules/pypdfium2/fix-cc-detection.patch
new file mode 100644
index 000000000000..e01cc90901f5
--- /dev/null
+++ b/pkgs/development/python-modules/pypdfium2/fix-cc-detection.patch
@@ -0,0 +1,25 @@
+diff --git a/src/ctypesgen/__main__.py b/src/ctypesgen/__main__.py
+index 23ee014..2d0cfc1 100644
+--- a/src/ctypesgen/__main__.py
++++ b/src/ctypesgen/__main__.py
+@@ -89,17 +89,9 @@ def main_impl(args, cmd_str):
+         assert _is_relative_to(args.output, args.linkage_anchor)
+     
+     if args.cpp:
+-        assert shutil.which(args.cpp[0]), f"Given pre-processor {args.cpp[0]!r} is not available."
+-    else:
+-        if shutil.which("gcc"):
+-            args.cpp = ["gcc", "-E"]
+-        elif shutil.which("cpp"):
+-            args.cpp = ["cpp"]
+-        elif shutil.which("clang"):
+-            args.cpp = ["clang", "-E"]
+-        else:
+-            raise RuntimeError("C pre-processor auto-detection failed: neither gcc nor clang available.")
+-    
++        print("cpp argument ignored for nix build")
++    args.cpp = ["@cc@", "-E"]
++ 
+     # Important: must not use +=, this would mutate the original object, which is problematic when default=[] is used and ctypesgen called repeatedly from within python
+     args.compile_libdirs = args.compile_libdirs + args.universal_libdirs
+     args.runtime_libdirs = args.runtime_libdirs + args.universal_libdirs