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Significance Analysis of INTeractome (SAINT) is a statistical method for probabilistically scoring protein–protein interaction data from affinity purification-mass spectrometry (AP-MS) experiments. The utility of the software has been demonstrated in many protein–protein interaction mapping studies, yet the extensive testing also revealed some practical drawbacks. In this paper, we present a new implementation, SAINTexpress, with simpler statistical model and quicker scoring algorithm, leading to significant improvements in computational speed and sensitivity of scoring. SAINTexpress also incorporates external interaction data to compute supplemental topology-based scores to improve the likelihood of identifying co-purifying protein complexes in a probabilistically objective manner. Overall, these changes are expected to improve the performance and user experience of SAINT across various types of high quality …