Two patients with spontaneously acquired factor-VIII-C inhibitors were treated with high-dose i.v. gammaglobulin. Minimal inhibition of anti-VIII-C activity was demonstrated in vitro in one patient when i.v. gammaglobulin was mixed directly with his plasma. In neither patient, however, was there any significant reduction in titer of antifactor VIII-C after i.v. gammaglobulin administration, nor was there any shortening of the aPTT or reduction in bleeding. The possible mechanisms of the previously reported salutary benefits of high-dose i.v. gammaglobulin in patients with spontaneously acquired factor-VIII inhibitors as well as the potential reasons for failure in our patients are discussed. Our cases demonstrated that high-dose i.v. gammaglobulin is not uniformly successful in the treatment of patients with acquired factor-VIII-C inhibitors. The true frequency of clinically significant responses will require further clinical trials.