Alpha-interferon (IFN-α) is an effective treatment for chronic hepatitis C, but only 20% to 30% of patients are apparently cured with the currently recommended schedule of 3 MU given three times a week for 6 months. To evaluate the efficacy of more aggressive treatment regimens, we have conducted a randomized trial in 174 patients with chronic hepatitis C using three different schedules: (1) 12-month treatment starting with 6 MU/three times a week and decreasing the dose on the basis of serum alanine transaminase (ALT) activities (group A: 59 cases); (2) fixed dose of 3 MU three times a week for 12 months (Group B: 61 cases), (3) fixed dose of 6 MU three times a week for 6 months (Group C: 54 cases). Patients were evaluated during therapy for biochemical and virological response and followed for at least 12 months after therapy to assess long-term efficacy and liver histological outcome. The genotype of infecting HCV was also analyzed in all patients, and predictors of response were determined by multivariate analysis. Serum ALT became normal during therapy in 76% of patients (95% confidence interval [CI]: 63 to 86), 65% (CI: 52 to 77), and 74% (CI: 60 to 85) in groups A, B, and C, respectively (P = NS). The corresponding figures for sustained response 12 months after therapy were 49% (CI: 36 to 62), 31% (CI: 20 to 44), and 28% (CI: 16 to 42) (A vs. B, P = .06; A vs. C,P = 0.03). Eighty-six percent of patients with sustained response cleared HCV-RNA from serum, and 72% improved histologically. Patients infected with HCV genotypes 2a and 3 had higher sustained response rates than those with Ib, independent of treatment schedule. In patients infected with genotype 1b, the rate of sustained response was related to dose and duration of therapy being 28% with schedule A, 16% with schedule B, and 9% with schedule C. Multivariate analysis indicated that younger age (P = .016), shorter disease duration (P = .003), and infection with HCV genotypes 2a (P = .0017) and 3 (P = .0083) were independent predictors of sustained response. These results indicate that sustained response to IFN-α in chronic hepatitis C is affected by dose and duration of therapy, particularly in patients infected with HCV genotype 1b. (Hepatology 1995; 22:700–706.)