The long-term benefit of interferon therapy in chronic hepatitis C is limited. During therapy, serum alanine aminotransferase (ALT) levels decrease to normal and hepatitis C virus (HCV) RNA decreases in 40% to 60% of patients. However, most patients relapse after therapy withdrawal, so that no more than 15% to 25% achieve a sustained response. Re-treatment has been evaluated in studies using different regimens and forms of alpha interferon in different cohorts of patients at different times after initial therapy. Both end-of-treatment and sustained responses to re-treatment correlate with the type of response achieved during the initial course. Patients who do not respond or have only a partial response to the initial course of interferon have an extremely low rate of sustained response when re-treated, independently of the regimen used. Combining data from 13 studies, sustained responses occurred in no patients who were re-treated with 3 million units (MU) three times weekly for 6 months, and in only 2% to 3% of patients re-treated with higher doses and/or for longer periods. In contrast, a significant number of patients who responded during the initial course but subsequently relapsed have a sustained response when re-treated with interferon alone. Combining data from 11 published studies on patients who relapsed after an initial course, sustained responses occurred in 15% (95% confidence interval [CI], 10%-20%) of patients re-treated with 3 MU three times weekly for 6 months, in 29% (CI, 17%-40%) re-treated with a higher dose for 6 months, and in 43% (CI, 34%/50%) re-treated for at least 12 months. On the other hand, patients who relapsed after a 12-month course of interferon had only 4% rate (range, 0%-8%) of sustained response when re-treated. The best predictor of sustained response to re-treatment in patients who had relapsed was a negative serum HCV-RNA test by polymerase chain reaction at the end of the first course. These results, which have been confirmed in a recent prospective, randomized controlled trial, indicate that nonresponders to interferon should not be re-treated with interferon alone, whereas patients who relapse after a 6-month course of alpha interferon therapy have an indication to be re-treated for at least 12 months, especially if serum HCV RNA was negative at the end of the first course of treatment.