Members of the herpes virus family and hepatitis B virus (HBV) have been implicated as etiologic agents in non-A, non-B (NANB) fulminant hepatic failure (FHF), but the frequency of infection with these agents has not been established using appropriate controls. To examine this issue, we studied 50 NANB FHF patients and 104 liver transplant recipients from North America and Europe. Hepatic DNA was analyzed by polymerase chain reaction (PCR) for evidence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus I (HSV I) and II (HSV II), varicella-zoster virus (VZV), and human herpes virus-6 (HHV-6) nucleic acid sequences. The prevalence of HBV was assessed in North American subjects only. HSV I, HSV II, VZV, and HHV-6 viral sequences were not observed in any samples. Three of 50 FHF (6%) and 14 of 104 control patients (13%) were positive for CMV DNA. Two of 50 FHF (4%) and 10 of 104 control patients (10%) had EBV DNA, and HBV DNA was observed in 3 of 10 North American FHF patients (30%) and 3 of 59 controls (5%) without serum markers for HBV infection. The finding of HBV DNA in the liver of seronegative controls from North America but not Europe suggests that occult hepatitis B sequences in patients with NANB FHF may simply reflect geographic differences. The majority of cryptogenic FHF cases cannot be attributed to infection with herpes viruses or HBV.