Precipitating antibodies directed toward human F.VIII/WF were found in the plasma of four out of 17 multitransfused patients with severe, homozygous-like VWD. The familial incidence was illustrated by the development of these antibodies in three patients from the same kindred. Such antibodies, titrated with newly developed quantitative assays of anti-VIIIR:Ag and anti-VIIIR:RCo, were directed toward only these components of F.VIII/WF. VIII:C was neutralized in a time-independent manner in plasma and was not inactivated when separated from F.VIII/WF by solid-phase PE absorption. Plasma, serum, or immunoglobulin reacted in precipitation systems (immunodiffusion, EID, CIE) with human VIIIR:Ag, with some degree of cross-reactivity toward VIIIR:Ag from other mammalian plasmas. When used in IRMA, these antibodies demonstrated the same abnormalities as heterologous antisera in variant VWD: decreased binding affinity or nonparallelism of the dose-response curves. They are polyclonal IgG with both kappa and lambda light chains. It is suggested that in some patients with severe homozygous-like VWD, the synthesis of the component of F.VIII/WF carrying VIIIR:Ag and VIIIR:RCo is suppressed whereas VIII:C production is not completely abolished.