 <p>A couple of things to check.</p> <ul> <li><p>The pyenv tool doesn't install Python with a shared library by default. That could result in problems as mod_wsgi wants a shared library. You need to explicitly tell pyenv to build Python with a shared library.</p></li> <li><p>A home directory on many Linux systems is not readable to other users. When mod_wsgi is being initialised, it is running as the Apache user and will not be able to see inside of the home directory. There isn't an issue when the mod_wsgi module is loaded by Apache as Apache is running as root at that point.</p></li> </ul> <p>There are other issues with your configuration where don't follow best practices, but the above, especially the second item is likely the cause of your problem.</p>