If you want to mainly base your code on the .NET framework, I'd highly recommend IronPython vs Python.NET. IronPython is pretty much native .NET - so it just works great when integrating with other .NET langauges.
Python.NET is good if you want to just integrate one or two components from .NET into a standard python application.
There are notable differences when using IronPython - but most of them are fairly subtle. Python.NET uses the standard CPython runtime, so this Wiki page is a relevant discussion of the differences between the two implementations. The largest differences occur in the cost of exceptions - so some of the standard python libraries don't perform as well in IronPython due to their implementation.
While agreeing with the answers given by Reed Copsey and Alex Martelli, I'd like to point out one further difference - the Global Interpreter Lock (GIL). While IronPython doesn't have the limitations of the GIL, CPython does - so it would appear that for those applications where the GIL is a bottleneck, say in certain multicore scenarios, IronPython has an advantage over Python.NET.
From the Python.NET documentation:
Important Note for embedders: Python is not free-threaded and uses a global interpreter lock to allow multi-threaded applications to interact safely with the Python interpreter. Much more information about this is available in the Python C API documentation on the
When embedding Python in a managed application, you have to manage the GIL in just the same way you would when embedding Python in a C or C++ application.
Before interacting with any of the objects or APIs provided by the
Python.Runtimenamespace, calling code must have acquired the Python global interpreter lock by calling the
PythonEngine.AcquireLockmethod. The only exception to this rule is the
PythonEngine.Initializemethod, which may be called at startup without having acquired the GIL.
When finished using Python APIs, managed code must call a corresponding
PythonEngine.ReleaseLockto release the GIL and allow other threads to use Python.
ReleaseLockmethods are thin wrappers over the unmanaged
PyGILState_Releasefunctions from the Python API, and the documentation for those APIs applies to the managed versions.
Another issue is IDE support. CPython probably has better IDE support at present than IronPython - so this may be a factor in the choosing of one over the other.