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Protein–protein interactions are essential for biological function, but structures of protein–protein complexes are difficult to obtain experimentally. To derive the protein complex of the DNA-repair enzyme human uracil-DNA-glycosylase (hUNG) with its protein inhibitor (UGI), we combined rigid-body computational docking with hydrogen/deuterium exchange mass spectrometry (DXMS). Computational docking of the unbound protein structures provides a list of possible three-dimensional models of the complex; DXMS identifies solvent-protected protein residues. DXMS showed that unbound hUNG is compactly folded, but unbound UGI is loosely packed. An increased level of solvent protection of hUNG in the complex was localized to four regions on the same face. The decrease in the number of incorporated deuterons was quantitatively interpreted as the minimum number of main-chain hUNG amides buried in the protein–protein interface. The level of deuteration of complexed UGI decreased throughout the protein chain, indicating both tighter packing and direct solvent protection by hUNG. Three UGI regions showing the greatest decreases were best interpreted leniently, requiring just one main-chain amide from each in the interface. Applying the DXMS constraints as filters to a list of docked complexes gave the correct complex as the largest favorable energy cluster. Thus, identification of approximate protein interfaces was sufficient to distinguish the protein complex. Surprisingly, incorporating the DXMS data as added favorable potentials in the docking calculation was less effective in finding the correct complex. The filtering method has greater flexibility, with the capability to test each constraint and enforce simultaneous contact by multiple regions, but with the caveat that the list from the unbiased docking must include correct complexes.