Object: The aim of this study was to examine the efficacy and the changes of amino acid sequences of the interferon sensitivity-determining region (ISDR) by prolonged interferon (IFN) treatment in patients who have serum hepatitis C virus (HCV)-genotype lb and a high level of serum HCV-RNA. Methods: Inclusion criteria were biopsy-proven chronic hepatitis, positive HCV-RNA,and an abnormal serum aminotransferase level. Twenty-five patients received 6 MU of natural IFN-oc daily for 8 weeks, followed by three times weekly for 40 weeks (1,056 MU). One patient was withdrawn from the study due to IFN side effects. Therefore, the remaining 24 patients (group 1) were studied the efficacy of IFN administration and changes of ISDR. As a control, 22 patients (group 2) treated with natural IFN-a for 24 weeks for the same period were studied retrospectively.Patients were defined as complete responders (CR) if serum HCV-RNA levels were negative for 6 months after IFN therapy. Results: According to this criterion, CR was 25% (6/24) in group 1 and 9.1% (2/22) in group 2. The normalization rates of alanine aminotransferease (ALT) for six months after termination of IFN was 41 % (10/24) in group 1 and 18.2% (4/22) in group 2. Regarding the changes of ISDR in patients with no CR, the change rates ofISDR were 16.7% (3/18) in group 1 and 10% (2/20) in group 2. Conclusion: We concluded that prolonged IFN therapy was effective for patients with HCV-genotype lb and a high level of serum HCV-RNA. (Internal Medicine 38: 461-466, 1999)