Microbial IgA proteases cleave human serum IgA1 immunoglobulin, but human secretory IgA is resistant to hydrolysis. We have found this resistance to be due to an inhibition of protease activity that is mediated by the Fab region of secretory IgA. The IgA proteases of the genus Neisseria are more sensitive to inhibition than is the protease of Streptococcus sanguis. There is also a serum inhibitor of Neisseria proteases that co-chromatographs with IgG. Monoclonal (myeloma) human IgG proteins and plasma protease inhibitors such as alpha-1-antitrypsin and alpha-2-macroglobulin do not inhibit. Human sera do not contain inhibitor to S. sanguis protease activity. We conclude that microbial IgA proteases are subject to inhibition by IgA in secretions and IgG in serum, and this activity is most consistent with being an anti-enzyme antibody. The insensitivity of S. sanguis IgA protease to inhibition is unexplained but provides further evidence that the IgA proteases are structurally diverse.