Protein-protein interaction studies can provide valuable insight into protein function. One of the most practical and high-yielding approaches is immunoprecipitation of a bait protein followed by mass spectrometry to identify co-precipitating proteins. Here we describe an effective and simplified version of this method that can be performed in most laboratories using standard laboratory equipment (apart from the mass spectrometer). We further demonstrate the utility of this method to identify proteins that specifically interact with mutant forms of the tumor suppressor protein, p53.