A new algorithm is reported to assist with the identification of protein interaction domains by comparing pairs of MALDI mass spectra recorded for protein digests treated with a binding partner versus an untreated control. Known as PRISM, for protein interactions from the spectra of masses, the algorithm imports m/z versus peak area data directly from a pair of MALDI mass spectra recorded for the control and reaction sample. The algorithm is shown to be able to successfully identify antigenic determinants for protein antigens within mixed protein digests. The algorithm has general utility for the comparative analysis of differences within any two mass spectra of any type and is easily implemented using a simple, intuitive graphical user interface (GUI).