The effects of interferon therapy on liver histologic findings were assessed in a randomized controlled trial consisting of 80 patients with chronic non-A,non-B hepatitis. Twenty-eight patients received 1 million units of recombinant interferon alpha-2b; 25 patients received 3 million units, subcutaneously, three times a week for 24 weeks; and 21 patients were observed as untreated controls; all of them underwent liver biopsy within 6 months from the beginning of the study and on the last day of therapy. Six patients were withdrawn from the study because of inadequate liver biopsy specimens. Alanine aminotransferase levels were determined before, during, and after therapy. For each biopsy, a semiquantitative score of histologic features, the histologic activity index, and the overall histologic assessment were performed. Ninety-five percent of patients tested positive for hepatitis C virus antibody. Portal inflammation, piecemeal and spotty necrosis, and bile duct proliferation were significantly decreased in patients with normalized alanine aminotransferase. The effectiveness of therapy was dose dependent: piecemeal and spotty necrosis and the histologic activity index showed a significant decrease only in 3-million-unit-treated patients. Hepatocellular degeneration and fibrosis did not change significantly after treatment.