Fulminant hepatic failure (FHF) is an established indication for liver transplantation. A pretransplant diagnosis of FHF may be a risk factor for subsequent development of cytomegalovirus (CMV) infection, although the mechanism of this association is not understood. FHF is associated with very high levels of tumor necrosis factor alpha (TNF-alpha), and TNF-alpha may directly promote viral replication. We have used the polymerase chain reaction (PCR) to examine sequentially collected buffy coats from 106 consecutive adult liver transplant recipients. PCR evidence of CMV replication was found for 13 of 18 patients who underwent transplantation for FHF (c.f. 23/88 non-FHF patients; P < .01). Ten of 12 patients who received transplants transplanted for fulminant seronegative hepatitis were buffy-coat PCR-positive, sometimes during the first posttransplant week. TNF-alpha was measured by enzyme-linked immunosorbent assay in selected sera, and results were examined in the context of a quantitative PCR assay. Serum TNF-alpha levels increased and decreased in concert with viral titers. High levels of TNF-alpha were not found in the early posttransplant period. We conclude that FHF (in particular, seronegative hepatitis) is associated with enhanced CMV replication in the posttransplant period. Results also suggest that viral replication may be enhanced before transplantation. These patients may be at special risk for development of symptomatic CMV infection.