Interferon (IFN) is the only drug that has been approved by the FDA for therapy of chronic hepatitis C. However, optimal dose and duration of therapy are still controversial. This study compares the effectiveness of treatment of chronic hepatitis C patients with 3 vs. 5 million units (MU) of recombinant alpha-interferon 2-b three times per week. We also evaluated the relapse rate with a shorter 12 week-course of therapy in those patients who had normalization of aminotransferases by week 12. Seventy-five patients were randomized to receive either 3 vs. 5 MU of IFN; seventy-two completed the study. A complete response was seen in 11/35 (31%) of those treated with 5 MU vs. 13/37 (35%) in the 3 MU dose (p = 0.74). Patients were followed after IFN was withdrawn and only 2 had persistently normal aminotransferases. Analysis of multiple variables was done to predict response to IFN and only elevations of GGT, ferritin and alkaline phosphatase were found to be predictors of a poor response. Therefore, we recommend initial therapy with 3 MU of IFN for a longer period than 12 weeks in patients who show a response.