Chronic infection with hepatitis C virus (HCV) may result in cirrhosis, liver failure, and hepatocellular carcinoma. A minority of patients have a sustained response to antiviral therapy, and nonresponders remain at risk of developing progressive liver disease. We conducted a randomized, controlled trial of therapy with the combination of interferon (IFN) and ribavirin in patients with chronic hepatitis C who had not responded to an initial course of therapy with IFN alone. A total of 124 patients were randomized to receive the combination of IFN and ribavirin for either 24 or 48 weeks and followed for an additional 24 weeks after stopping therapy. Thirty-eight treated patients (30.6%) achieved a sustained virologic response (undetectable HCV RNA at the 24-week follow-up point). This was associated with significant improvement in necroinflammatory activity noted on liver biopsy. Interestingly, there was not a statistically significant difference in response rates based on the duration of treatment; HCV genotype was the strongest predictor of a sustained response. Sustained responses were noted even in patients with poor predictive factors, including those with advanced hepatic fibrosis or cirrhosis, high levels of HCV RNA in serum, and those infected with HCV genotype 1. Considerable advances have recently been made in the therapy of chronic hepatitis C. While rates of sustained virologic response to interferon (IFN) alone have averaged between 10% and 15%, they have increased to 35% to 40% with the combination 1,2 of IFN and ribavirin. This combination has replaced the use of IFN alone as the first-line therapy in patients with chronic hepatitis C. One category of patients who seem to respond very well to IFN and ribavirin is the group that had an initial response to IFN, but then had a relapse of the hepatitis C viral infection after the IFN was stopped. Retreatment of these "relapsers" results in sustained virologic response rates approaching 70%. 3 However, similar benefit has not been observed in re-treating those patients who did not respond to their initial course of IFN, i.e., "nonresponders." They have persistence of hepatitis C virus (HCV) RNA with or without elevations in serum transaminases, even after a full course of IFN therapy. These patients often have more advanced hepatic fibrosis than those who responded to therapy and are more often infected with HCV genotype 1. 4 Thus, they remain at considerable risk of progression of their liver disease to cirrhosis, liver failure, and perhaps even hepatocellular carcinoma.Preliminary data on re-treatment of small numbers of nonresponders with the combination of IFN and ribavirin do not indicate a clear pattern of response. We therefore conducted a randomized, controlled trial of re-treatment with this combination in nonresponders to IFN, comparing the benefits of 24 versus 48 weeks of therapy in a large number of patients. PATIENTS AND METHODSPatients were offered participation in this study if they had chronic hepatitis C and had received at least 12 we...