This is a proposal for the Liver Center at BIDMC to act as a clinical trials center in a multicenter collaborative program to examine resistance to antiviral therapy in African Americans with hepatitis C. HCV is a common problem in the US with almost 4 million individuals exposed to the virus. HCV is the commonest cause of cirrhosis and liver cancer in the US. Almost 6% of African Americans have HCV and there response to Interferon based antiviral therapy is only 50% that of non-HIspanic whites. This study will examine the mechanism of viral resistance in African Americans to PEG-Interferon combined with ribavirin and examine the factors potentially responsible for viral resistance. The specific Aims are to 1) Confirm that there is a difference in sustained viral clearance between AA and whites; 2) Identify factors that effect response to antiviral therapy; 3) determine the role of HCV viral kinetics during therapy on subsequent sustained viral clearance; 4) identify virological, immunological-and host genetic factors that determine viral clearance. Approximately 400 patients will be treated with PEG-IFN and ribavirin for 48 weeks and then followed for a further 48 weeks to determine sustained viral eradication. Pretreatment variables will be correlated with viral clearance. Specimens of liver tissue and serum will be collected for basic studies on viral resistance. These studies should help determine the best therapy for AA with HCV.