Objective: Most of chronic hepatitis C patients with HCV-genotype 1 and a high virus load fail to eradicate the HCV-RNA by the interferon (IFN) or IFN/ribavirin therapy. But in these patients, IFN is often effective with regard to normalization of alanine aminotransferase (ALT). We had therefore the following two randomized controlled clinical trials to evaluate the effect of IFN which reduce ALT and maintain normalization of ALT. One approach (study 1) was to compare the efficacy of a 6 month course of three different dosages of recombinant IFN-alpha-2a in patients with chronic hepatitis C associated with HCV-genotype 1b and a high serum HCV-RNA level of more than 1 Meq/ml. Another approach (study 2) was to make clear the significance of an additional 6 month course of IFN in patients who had biochemical response during the first 6 month course of IFN (study 1). Methods: (1) Study 1; 45 patients with HCV-genotype 1b and a high serum HCV-RNA level of more than 1 Meq/ml were randomly assigned into three equal groups; group 1 was treated with 3 million units (MU), group 2 with 6 MU and group 3 with 9 MU. They were treated with IFN 3 times weekly for 6 months. Biochemical response was defined as normalization of ALT at the 6 month after initiation of IFN; (2) Study 2; Subsequently, of 23 patients with biochemical response by the first study, 22 were randomly assigned to two groups; patients in group A were continued to receive 3 MU of IFN-alpha-2a three times a week for an additional 6 months and patients in group B were discontinued IFN therapy. Results: (1) Study 1; One patient in group 1, three in group 2 and five in group 3 withdrew from IFN therapy because of IFN-related side-effects. Biochemical response was 10 (66.7%) patients of group 1,8 (53.3%) of group 2 and 5 (33%) of group 3 by the intention-to-treat (ITT) analysis. The biochemical response rate in group 1 was slightly higher than that in other two groups by the Cochran Armitage two-tailed test (P=0.066). With respect to serum HCV-RNA level, one patient in group 1, six patients in group 2 and four patients in group 3 became negative for HCV-RNA by reversed transcription nested-polymerase chain reaction (RT nested-PCR) at the end point of first 6 month course of IFN; (2) Study 2; The maintenance rate of ALT normalization was 88.9% (9/11) in group A and 11.1% (2/11) in group B. The maintenance rate of ALT normalization in group A was significantly higher than that in group B by the Fisher exact's test (P=0.0089). With respect to serum HCV-RNA level by RT nested-PCR, four patients in group A had negative HCV-RNA at the end of an additional IFN therapy. On the other hand, all the patients in group B had positive HCV-RNA at the same time. Conclusion: Our data suggested that a prolonged IFN therapy using a dose of 3 MU of IFN-alpha-2a is safe strategy to reduce ALT and to maintain ALT normalization in patients with HCV-genotype 1b and a high serum HCV-RNA level of more than 1 Meq/ml.