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Hepatitis C is a major health problem worldwide, yet very little research has been performed to assess the knowledge base and practice patterns of primary care physicians (PCPs) regarding hepatitis C. The aim of this study is to determine the knowledge base and practice patterns of a nationwide cohort of PCPs. A survey was developed to assess the knowledge of PCPs regarding risk factors for hepatitis C, management of hepatitis C patients and attitude regarding testing for hepatitis C. The survey was mailed to 4000 PCPs in the USA. A total of 1412 (39%) PCPs completed the survey. The vast majority, > 90%, of PCPs correctly identified the most common risk factors for hepatitis C. However, only 59% indicated they ask all patients about hepatitis C risk factors, 70% reported they test all patients with hepatitis C risk factors and 78% test all patients with elevated liver enzymes for hepatitis C. Most (72%) PCPs would refer an HCV-positive patient with elevated aminotransferase but only 28% would refer an HCV-positive patient with normal aminotransferase to a specialist. One-fourth of the PCPs did not know what treatment to recommend for hepatitis C patients. Our data suggest that hepatitis C patients may be underdiagnosed and under-referred. Specific educational initiatives and practice guidelines for PCPs are needed to optimize the recognition of patients at risk for hepatitis C and to ensure appropriate testing and referral.