Fulminant hepatic failure (FHF) in the absence of serum markers of hepatitis A (HAV) or B (HBV) infection or another cause is called non-A, non-B (NANB) FHF. The pathogenetic role of viral infection in NANB FHF remains controversial. To better define this relationship, we studied patients who underwent orthotopic liver transplantation (OLT) for FHF. Thirty-six patients with FHF underwent transplantation between 1987 and 1992. Pre-OLT serum was available for 24 patients, 14 with NANB FHF (all female; mean age, 32 years), and 10 (3 males, 7 females; mean age, 20 years) with a defined origin for FHF who formed the control group. Sera were tested using polymerase chain reaction for HAV, HCV, HDV, and HEV RNA and HBV DNA, and also serologically for antibodies to these viruses. In the NANB group, pre-OLT serum was negative for all viruses tested. Four patients in the control group had HBV serologically, 2 with HBV DNA in serum. One of these 4 also had hepatitis C and one hepatitis D infection. There was no difference in intensive care unit or hospital stay between the groups. The only significant difference in laboratory data was for peak creatinine pre-OLT (0.94 mg/dL in NANB v 1.62 mg/dL; P < .05). Two patients in the NANB groups and 3 in the control group required early retransplantation for graft primary nonfunction. One case of NANB FHF appeared to recur at 6 months but not after subsequent retransplantation. NANB FHF is not associated with hepatitis A, B, C, D, or E in plasma. It has a later age of onset but a similar clinical course to other forms of FHF and appears to preferentially affect women.