ABSTRACT Conventional database search methods for proteomics struggle when tasked to identify dozens or hundreds of modifications simultaneously. Open or error-tolerant searches can address this limitation, but at the cost of increased difficulty in downstream interpretation of the results and quantification. We and others have previously described “mass offset” or multi-notch searches that sit in between closed and open searches, allowing simultaneous search for hundreds of modifications with more straightforward downstream interpretation than open search. The original mass offset searches were closer to open search, lacking the ability to restrict modifications to specific amino acids. Here, we describe a new “detailed” mass offset (DMO) search implemented in the MSFragger search engine, which allows each mass offset to have its own site restrictions and fragmentation rules. The benefits of DMO search over existing mass offset searches are shown with three example searches of complex modification sets: nearly one hundred post-translational modifications, fast photochemical oxidation of proteins (FPOP)-derived modifications, and amino acid substitutions. The DMO search further improves the interpretability of results by reducing ambiguity in site localization, particularly when modifications have overlapping masses, and provides benefits that scale with the complexity of the search.