It is unclear whether hepatitis G virus (HGV) can lead to chronic liver disease and cirrhosis. Eighty-nine patients with end-stage liver disease undergoing liver transplantation were studied: 50 were diagnosed as having cryptogenic cirrhosis while 39 had nonviral chronic liver disease. Five (10%) in the former and 1 (2.6%) in the latter group (not significantly different) were positive for HGV RNA in serum. All 6 HGV-infected patients were negative for the presence of the HGV RNA minus strand in the liver when tested with a strand-specific Tth-based reverse transcription-polymerase chain reaction, and 5 were positive for the presence of the plus strand, albeit at low levels. This implies that the liver is not the primary replication site for HGV, at least in a significant proportion of patients. Absence of liver replication explains the reported lack of association between HGV infection and liver pathology encountered in many clinical settings.