Chronic Hepatitis C can progress to end-stage liver cirrhosis or hepatocellular carcinoma. Interferon (IFN) therapy is effective in clearing the hepatitis C virus and in improving liver histology, however, few patients maintain a sustained response (SR) after IFN withdrawal. Immediate retreatment with IFN is therefore considered to be both effective and necessary, especially for patients who do not respond to the initial course of IFN therapy. All 145 patients included in the present study underwent liver biopsy, followed by a first treatment course with various IFNs (alpha2a, alpha2b, alpha, OIF or beta). If hepatitis C virus (HCV) RNA was positive after the first treatment, the patient was assigned to one of 3 groups, depending on whether his or her alanine transaminase (ALT) level was normalized (incomplete response, IR), partially responsive (PR), or non-responsive (NR). After an observational interval of 6 to 76 months, a second IFN treatment was initiated with a higher dose or the same dose of the same IFN for the IR group, and with a different IFN for the PR and NR groups. At 6 months after retreatment with IFN, the overall efficacy of the retreatment was 29.7%. In the case of the IR group, who received the same IFN, the overall efficacy was 45.2%. In patients identified as non-SR after the first treatment, who received a different type of IFN for retreatment, the overall efficacy was 18.6%. Anti-IFN antibody was not detected in most of the breakthrough cases. For some IR patients, retreatment with the same IFN was effective. Anti-IFN antibody was mostly negative, indicating that the same IFN can be used in both the first treatment and retreatment to obtain an SR. Switching to a different IFN was effective for some PR and NR patients, suggesting that changing IFN for such cases is a good therapeutic choice.