Annika, I too just started with pythonnet. What I'm learning is that the compilation of pythonnet needs to match that of the .dll you are trying to load. So, for instance, how was your .dll built (for .NET 4? 3.5? ..). Check that. In my case I had to build pythonnet targeted for .NET 4 but it caused many other problems with underlying imports of pure CPython. I made a recent post on the issue for IPython: http://wiki.ipython.org/Cookbook/python.NET Maybe that will help!