Antibodies endowed with hydrolytic properties have been described in humans for over a decade in a variety of pathological conditions such as systemic lupus erythematosus (SLE), autoimmune thyroiditis, asthma, and Bence Jones disease. Although the identified target substrate molecules have always been autoantigens (i.e., DNA, thyroglobulin, vasoactive intestinal peptide), a direct role of hydrolysis of the autoantigen in pathology of the disease has not been clearly documented. We have described in multitransfused patients with hemophilia A the presence of anti-factor VIII (FVIII) IgG antibodies that hydrolyze FVIII. The estimated kinetic parameters derived for FVIII cleavage by anti-FVIII antibodies are in line with the previously described catalytic antibodies. The identified cleavage sites are evenly spread throughout the FVIII molecule and are located after an arginine or a lysine in most cases. We have recently shown that the catalytic antibodies are highly prevalent among hemophilia A patients with FVIII inhibitors. Catalytic antibodies to FVIII are the first example where the hydrolysis of the target molecule by hydrolytic antibodies may be directly relevant to the etiology of the disease. The characterization of FVIII inhibitors as site-specific proteases may provide novel strategies in the design of therapy against FVIII inhibitors in patients with hemophilia A. © 2002 Elsevier Science B.V. All rights reserved.