Of all nonhemophilic patients with acquired factor VIII:C (FVIII:C) inhibitors, as many as 87% suffer from hemorrhagic complications, and approximately 22% die as a result. Immunosuppressive therapy reduces or eradicates the inhibitor in 50-80% of patients, but a significant proportion remain refractory to such treatment and have a continued need for replacement therapy to manage bleeding complications. The possibility that porcine FVIII:C might fulfill this role has not been thoroughly investigated although limited data are available for patients with congenital hemophilia, which may offer some guidance. We recently reported the successful treatment with porcine FVIII:C over 2-8.5 years in five congenital hemophilia patients with high-level inhibitors initially lacking measurable cross-reactivity to porcine FVIII:C. One of four patients who developed transient, specific antiporcine inhibitors became refractory to treatment. Three further patients' antibodies demonstrated as much as 30% cross-reactivity but tolerated porcine FVIII:C therapy on demand for 18-24 months, with good clinical effect and no significant anamnesis or other untoward reactions. All five of these patients with non-cross-reacting antibodies began therapy with porcine FVIII:C and eventually lost their original inhibitors against human FVIII:C during treatment with the porcine factor. Surprisingly, when human FVIII:C was then reintroduced in three patients there was no recurrence of inhibitor activity during 3-4 subsequent years. This finding suggests that porcine FVIII:C, when administered over some interval to congenitally hemophilic patients, can induce a state of specific immune-tolerance to the human factor. On the other hand, porcine FVIII:C therapy may not suppress acquired inhibitors in nonhemophiliacs, since there is no evidence that administration of human FVIII:C causes immune-tolerance in this group. Porcine FVIII:C can be administered safely for a period of years. Anamnestic responses are unusual in acquired hemophilia, and only 20% of patients develop specific antiporcine antibodies. Porcine FVIII:C may play an important part in the long-term management of inhibitors in either congenital or acquired hemophilia.