Injection drug users are at high risk for hepatitis C virus (HCV) infection. In Baltimore, Maryland, the prevalence of anti-HCV is greater among injection drug users who are black, human immunodeficiency virus (HIV) infected, have injected longer, have injected more frequently, and have injected cocaine than among other injection drug users. HCV infection occurs quickly after the initiation of injecting illicit drugs, with 78% of study participants anti-HCV positive after 2 years of injecting. The prevalence of anti-HCV among injection drug users does not appear to be related to socioeconomic factors or sexual practices. Some injection drug users remain free of anti-HCV even after years of injecting and serologic evidence of other bloodborne pathogens. Some of these injection drug users have HCV infection, demonstrated by HCV RNA in their sera. However, the basis for viral persistence in the absence of anti-HCV and for the absence of HCV infection in long-term drug users is not known. Further studies are indicated to determine the mechanism or mechanisms for the absence of anti-HCV in persons exposed to the virus, because the biologic basis for this condition may elucidate the elements missing in the immune response of the majority of HCV-exposed persons who acquire persistent infection. In addition, interventions to prevent HCV infections should be applied in populations at risk for injection drug use early or before drug use begins.