Sustained responses to interferon-alpha occur in 10% to 25% of patients with chronic hepatitis C, but the long-term outcome is not well defined. We evaluated the long-term clinical, histological, and virological outcomes of 10 patients with chronic hepatitis C who were treated between 1984 and 1987 with interferon-alpha-2b for 52 +/- 6 weeks (total doses of 492 +/- 116 MU). Before therapy, all 10 had hepatitis C virus (HCV) RNA, elevations of serum aminotransferases, and chronic hepatitis with fibrosis on liver biopsy. Clinical follow up was 6 to 13 years, and liver biopsies were done 5 to 11 years after initiation of therapy. HCV RNA was assayed by qualitative and quantitative reverse transcriptase-polymerase chain reaction assays. Among 5 patients who had a 6-month sustained response after therapy, all remained HCV RNA negative, and at last follow-up, 4 had normal and 1 minimally elevated serum aminotransferase levels. Liver biopsy specimens were nonreactive for HCV RNA, and all the patients showed improvements in both inflammation and fibrosis and were either normal or had mild, nonspecific inflammatory changes. Among 5 patients without a sustained response, all continued to have HCV RNA in serum and persistent or intermittent aminotransferase elevations. Liver biopsy specimens showed little or no change in necrosis and inflammation; all except 1 patient had progression of fibrosis scores or cirrhosis. All 5 patients had symptoms of chronic hepatitis, 1 underwent liver transplantation, and another had progressive hepatic decompensation. In conclusion, patients with a 6-month posttreatment virological response have a favorable long-term clinical and histological outcome.