To investigate whether interferon-alpha receptor (IFN-alpha Rc) expression was related to the effectiveness of interferon therapy in hepatitis C virus (HCV)-associated chronic liver disease (CLD). IFN-alpha Rc mRNA was investigated by reverse transcription polymerase chain reaction (RT-PCR) in liver biopsies and peripheral blood mononuclear cells (PBMCs) from 40 patients with HCV-associated CLD who subsequently received IFN-alpha therapy. IFN-alpha Rc mRNA in the liver was detected in 18 of 20 (90%) responders to IFN and in 5 of 20 (25%) non-responders (P < 0.01). In PBMCs, IFN-alpha Rc mRNA was detected in all patients regardless of response to IFN. Increased histological hepatitis activity and liver fibrosis were significantly related to the absence of IFN-alpha Rc mRNA. The HCV-RNA genotype showed no significant relationship to IFN-alpha Rc mRNA expression. Our results suggest that IFN-alpha Rc mRNA expression in the liver, but not in PBMCs, is closely associated with the effectiveness of IFN-alpha therapy in HCV-associated CLD.