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Senegal is a country with a high incidence of hepatocellular carcinoma (HCC). The role of the hepatitis B virus (HBV) in the genesis of HCC is well established. To evaluate the role of the hepatitis C virus (HCV) in the occurrence of HCC in Senegal, second-generation serologic tests were used to compare the prevalence of anti-HCV antibody in subjects with HCC and in controls without liver disease. A polymerase chain reaction assay was used to look for HCV RNA in sera from patients with HCC and anti-HCV antibody. HBV markers were assayed in all study subjects. Prevalences of anti-HCV antibody were 10.9% (7/64) in the HCC group and 5% (3/58) in the control group (NS). In the HCC group, anti-HCV antibody was found in 2.4% (1/42) of subjects positive for the hepatitis B antigen (HBsAg) versus 27.2% (6/22) of subjects negative for the HBsAg (p < 0.01). HCV RNA was detected in five of six anti-HCV-positive HCC patients. Prevalence of the HBsAg was 65.6% (42/64) in the HCC group versus 17.2% (10/58) in the control group (p < 10-8). Anti-HBV antibody was detected in 48.3% (28/58) of controls versus 6.3% (4/64) of HCC patients (p < 10-8). These data do not support a close epidemiologic association between the HCV and HCC in Senegal, where the HBV remains the main viral cause of HCC.