To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-α2b), the acute clearance of HCV after a single dose of either 3, 5, or 10 mIU of IFN-α was compared in patients with chronic hepatitis C. HCV-RNA levels following IFN-α administration were measured. At 24 hours, mean percentage serum viral reduction was 41.4%, 63.7%, and 85.5% for 3, 5, and 10 mIU, respectively (P < .001). At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9%, 61.9%, and 74.3%, respectively (P < .001), indicating that the drug effect diminishes before 48 hours. Regression analysis showed a positive correlation between dose and percent reduction of HCV-RNA levels (r = .6; P < .001). A mathematical model showed that such dose dependence is expected if IFN-α partially blocks viral production. Minimum clearance and production rates of HCV were estimated from measurements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rate constant of 2.8 per day, corresponding to a virion half-life of 0.3 days or less. A minimal estimate of the daily HCV production and clearance is 3.7 x 1011 virions per day, indicating a high rate of replication and turnover. These results indicate that there is a dose-dependent effect of IFN-α in clearance of HCV genotype 1. Because the virion production rate is very rapid and because the current recommended dose of IFN-α (3 mIU) is often ineffective, larger doses should be considered to treat genotype 1-infected patients.