Hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis and cirrhosis worldwide. Screening volunteer donors for antibody to HCV (anti-HCV) has reduced the risk of posttransfusion hepatitis C to less than 1.0% per recipient. Virtually all persons with acute HCV infection seem to become chronically infected, and an average of 67% acquire chronic liver disease with persistently elevated liver enzyme values. Among anti-HCV-positive blood donors, 70% to 90% are HCV RNA positive, but less than half have biochemical evidence of liver disease. The extraordinarily high rate of persistent infection observed in humans and the lack of protection against rechallenge with homologous HCV strains demonstrated in experimental studies in chimpanzees suggest that HCV fails to induce an effective neutralizing antibody response. This raises major concerns for the development of effective passive or active immunoprophylaxis against hepatitis C.