The limited efficacy of alpha interferon (IFN) monotherapy for hepatitis C virus (HCV) infection has led to the investigation of alternative treatment approaches, including combining interferons with other antiviral agents. In several small, pilot studies, the combination of IFN plus ribavirin was significantly more effective than IFN monotherapy for the initial treatment of HCV. The encouraging results from these studies provided the rationale for conducting two (one US, one International) large, multicenter, randomized, placebo-controlled clinical trials of IFN plus ribavirin therapy for the initial treatment of HCV patients. Of patients receiving therapy [corrected] for 24 weeks, 31% (US) and 35% (International) achieved sustained virologic remission with interferon plus ribavirin [corrected], compared with only 6% (US) receiving interferon [corrected] plus placebo. Sustained virologic response rates were improved in patients treated for 48 weeks (interferon plus ribavirin, 38% [US]; 43% [International] compared to interferon plus placebo, 13% [US]; 19% [International]) [corrected]. Improvement was also observed in terms of biochemical and histologic end points in those receiving combination therapy. Pretreatment variables (HCV genotype, viral burden, stage of fibrosis) were less important as predictors of treatment outcome in patients receiving combination therapy. The safety profile of combination therapy reflected the individual safety profiles of IFN and ribavirin, without synergism. Combination therapy with IFN plus ribavirin was more effective than IFN monotherapy for the initial treatment of HCV in terms of virologic, biochemical, and histologic end points. The combination appears to be well tolerated with a predictable safety profile.