Interferon has been shown to be an effective treatment for some patients with chronic hepatitis C. In this study, the value of retreatment of nonresponders to interferon was investigated. Thirty-eight patients with hepatitis C virus (HCV)-RNA-positive chronic hepatitis C who had been treated with beta-interferon but still showed an alanine aminotransferase (ALT) level > 50 KU upon completion of therapy were retreated with alpha-interferon. Eight patients (21.1%) had normalization of ALT levels for at least 6 months after the completion of retreatment. The factors related to normalization of ALT levels after interferon retreatment were studied. Of 16 patients with transient HCV-RNA negativity 1 month after the initial interferon therapy, 7 (43.8%) had a complete response, with normalization of ALT levels and undetectable HCV-RNA, more than 6 months after interferon retreatment. On the other hand, of the 22 patients with HCV-RNA activity 1 month after the initial interferon therapy, only 1 (4.5%) had a complete response. Multivariate analysis, using a multiple logistic model, indicated that a complete response to readministration of interferon was most strongly correlated to transient negative conversion for HCV-RNA after the initial course of treatment.