Hepatic expression of interferon-alpha (IFN-alpha) was examined by immunohistochemistry in 90 Chinese patients (M/F 67:23, age: 14-69) with a spectrum of hepatitis B virus (HBV)-related chronic liver diseases. Immunoreactive IFN-alpha was detected in sinusoidal cells in 79 patients (88%) and in mononuclear cells in 59 patients (65.6%). Patients with active liver diseases (chronic active hepatitis, active cirrhosis, N = 55) had a higher level of IFN-alpha expression compared to patients with inactive histology (N = 35; sinusoidal cells, P < 0.01; mononuclear cells, P < 0.01). Cytoplasmic HBsAg, nuclear HBcAg, and cytoplasmic HBcAg were detected in 79 (88%), 42 (47%), and 23 (27%) patients respectively. Expression of IFN-alpha in mononuclear cells correlated with the expression of cytoplasmic HBcAg (P < 0.05) but not with nuclear HBcAg or cytoplasmic HBsAg. When the patients were divided into four different phases according to the natural history of chronic HBV infection, patients in the active liver disease phase had higher IFN-alpha expression compared to the immunotolerant and late phase patients (P < 0.01). Using double immunohistochemical staining, both IFN-alpha and cytoplasmic HBcAg were frequently detected near inflammatory infiltrates but no correlation existed between the hepatic expression of HBsAg and IFN-alpha. These data indicate that IFN-alpha is expressed in the liver in HBV-related active liver diseases and that the reported suboptimal production of IFN-alpha by PBMC in HBV-related chronic active liver diseases may be due to a redistribution of the IFN-alpha-producing mononuclear cells into the liver, the site of inflammation.