A lthough human antibodies to Factor VIII inactivate its procoagulant activity, they do not form immunoprecipitates when tested with this antigen. To understand this observation, we have examined the interaction of normal human Factor VIII with four high-titer human anti-Factor VIII, two from transfused hemophiliacs and two “spontaneous” antibodies from nonhemophilic individuals. An estimate of the size of complexes formed by these antibodies has been obtained by agarose gel filtration of mixtures of anti-Factor VIII with cryoprecipitate. Complexed anti-Factor VIII was detected by the method of Allain and Frommel: acid dissociation of complexes at pH 3.5.Complexed anti-Factor VIII was detected in column fractions eluting between the void volume and those which correspond to the elution volume of human IgG. In contrast, Factor VIII procoagulant activity was restricted to void volume fractions when separations were carried out in antigen excess, and free anti-Factor VIII was limited to late-eluting fractions when separations were carried out in antibody excess. A small proportion of the complexed anti-Factor VIII was present in void volume fractions; the quantity was directly related to the ratio of antibody to antigen.Thus, although some complexed anti-Factor VIII is detected in void volume fractions, as would be expected for complexes formed with a very large plasma protein, most immune complexes elute in fractions that indicate interaction with a smaller antigen. These findings suggest that human anti-Factor VIII inactivates procoagulant activity by forming a complex with a small, apparently univalent, component of Factor VIII. This property may prevent immunoprecipitate formation.