Serial serum samples obtained from 27 patients with fulminant hepatic failure (FHF) in a variety of etiology were tested for anti-hepatitis C virus antibody (anti-HCV) with uses of two different assay systems. The incidence of anti-HCV in patients with FHF due to hepatitis B (Ortho test system; 7/11, 63.6%: Abbott test system; 9/11, 81.8%) was found to be significantly higher than that in acute HBV hepatitis (Ortho test system; 0/17, 0%) (P less than 0.001). In particular, all 3 post-transfusion HBV-FHF patients were positive for the antibody using both Ortho and Abbott test systems, and cut-off index in those patients was serially increased. On the other hand, cut-off index in anti-HCV positive patients with sporadic hepatitis A virus (HAV)- and HBV-FHF was high even prior to plasma exchange therapy, and gradually decreased. These results strongly suggest that in patients with post-transfusion HBV-FHF, HCV was superinfected over HBV and in the sporadic HAV- and HBV-FHF patients, HAV or HBV were co-infected over HCV carrier. In any events, co-infection and/or superinfection of HCV may play an important role in the development of this fatal disease.