To assess the effects of interferon treatment on chronic hepatitis C, histological changes long after treatment were compared with normalization of aminotransferases and seroconversion of hepatitis C virus RNA. Twenty one histologically proven chronic hepatitis C patients received alpha-interferon, 3 million units 3 times weekly for 12 months. Hepatitis C virus RNA was detected by reverse transcription/polymerase chain reaction method. Follow-up liver biopsies were performed 3 to 5 years after treatment. Fourteen of 21 (67%) patients showed normal aminotransferases for 3 to 5 years after treatment. HCV RNA seroconversion was observed in 12 of these patients. These responders showed improvement in histological activity indices and in histological findings. Two patients improved from chronic active hepatitis 2a to nonspecific changes, 1 from chronic active hepatitis 2a to portal fibrosis, 1 from chronic active hepatitis 2a to chronic persistent hepatitis and 1 from chronic active hepatitis 2b to chronic persistent hepatitis. Histological improvement of the liver correlated well with normalization of aminotransferases and seroconversion of hepatitis C virus RNA. These data indicate that complete histological resolution of chronic hepatitis C can be achieved by elimination of the virus with interferon treatment.