To determine the status of the tumor necrosis factor-alpha (TNFalpha) system in the liver in chronic hepatitis B virus (HBV) infection, hepatic expression of TNFalpha, its two receptors (TNFR-A, TNFR-B), HLA class I antigens (HLA-I), and HBV core antigen (HBcAg) were studied by immunohistochemistry in 24 patients with chronic HBV infection. TNFalpha was detected exclusively in the infiltrating mononuclear cells (MNC) in 19 of 24 patients. The expression of TNFalpha in infiltrating MNC correlated with serum markers of HBV replication and liver histology. TNFR were detected in hepatocytes, sinusoidal cells, and infiltrating MNC. The expression of TNFR correlated with liver histology (p < 0.01) but had no bearing on viral replication. There was a parallel expression of TNFalpha and TNFR (p < 0.01). Hepatocytic expression of HLA-I was increased, and this was related to liver histology but not with TNF alpha nor TNFR. These data indicate that the TNFalpha system is activated in the liver in chronic HBV infection.