Based on the most recent available crystal structures and biochemical studies of protease complexes of normal and mutant serine protease inhibitors (serpins), we have built models of the complexes: alpha 1-antitrypsin + human neutrophil elastase; alpha 1-antitrypsin Pittsburgh (358Met-->Arg) (Scott et al., J. Clin. Invest. 77:631-634, 1986) + tyrpsin; alpha 1-antitrypsin Pittsburgh (358Met-->Arg) + thrombin; and antithrombin + thrombin. All serpin sequences correspond to human molecules. The models show correct stereochemistry and no steric clashes between protease and inhibitor. The main structural differences in the serpins from the parent structures are: (1) the reactive center loop is inserted into the A-sheet as far as P12; (2) strand s1C is removed from the C-sheet; and (3) the C-terminus has changed conformation and interacts with the protease. In the absence of an X-ray structure determination of a serpin-protease complex, the demonstration that insertion of the reactive center loop into the A-sheet as far as P12 is stereochemically feasible provides structures of a protease-bound conformation of intact serpins with which to rationalize the properties of mutants, guide the design of experiments, and form a basis for further modeling studies, such as the investigation of the interaction of heparin with serpin-protease complexes.