Autoantibodies directed against factor VIII:C (FVIII:C) are associated with serious and often fatal bleeding. Efforts to suppress or abolish these antibodies with cytotoxic agents are frequently successful if antibody titer is not too high or there is an associated disease that undergoes remission. Corticosteroids alone may hasten antibody disappearance in almost half of patients, and cyclophosphamide is useful in those who are resistant to steroids administered alone or in combination. Patients refractory to these regimens may respond to a more aggressive approach using combination chemotherapy with cyclophosphamide, prednisone, and vincristine. Unfortunately, because of the rarity of this disorder, randomized, controlled trials have not been conducted either to compare treatments directly or to examine the factors presaging favorable outcomes. Recently, however, a multicenter trial comparing prednisone, cyclophosphamide, and the combination has been initiated, and some preliminary data from this investigation are presented. Approaches to the recognition and clinical management of this disorder also are described.