The recent cloning of the genome of a non-A, non-B hepatitis agent, designated the hepatitis C virus (HCV), has led to the development of an immunoassay for circulating HCV antibodies (anti-HCV). We used this immunoassay to investigate the possible association between HCV infection and hepatocellular carcinoma in black and white residents of Los Angeles County, California. Serum samples from 51 patients (12 black and 39 white) in Los Angeles County with hepatocellular carcinoma and 128 control subjects (1 black and 127 white) were tested for the presence of anti-HCV. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). Our results indicate that the presence of anti-HCV was a significant risk factor for hepatocellular carcinoma; the relative risk was 10.5 (95% confidence limits = 3.5, 31.3). Hepatocellular carcinoma risk was also significantly related to the presence of one or more of the hepatitis B virus (HBV) markers, primarily HBsAg and anti-HBc, and the relative risk was 7.0 (95% confidence limits = 3.1, 16.1). HCV and HBV independently contributed to hepatocellular carcinoma development. Significantly increased risk of hepatocellular carcinoma was demonstrated in individuals with HCV (relative risk = 4.8) or HBV (relative risk = 4.4) serologic markers alone. A synergistic effect on risk was observed when both hepatitis B and C viral markers were present in peripheral blood (10 cases vs. no controls). We estimate that approximately 47% of hepatocellular carcinoma occurring in black and white residents of Los Angeles County could be attributed to prior HCV and/or HBV infections: 9% were related to HCV alone, 20% to HBV alone, and 18% to occurrence of both HCV and HBV infections.