Hepatocellular carcinoma (HCC) exhibits a more than 50-fold variation in incidence worldwide. High-risk regions include East Asia and sub-Saharan Africa, while non-Asians in the United States constitute a low-risk population. We assessed 111 cases of histologically confirmed HCC and 128 community control subjects among non-Asians of Los Angeles County for the presence in serum of hepatitis B surface antigen (HBsAg), antibodies to HBsAg (anti-HBs), antibodies to the hepatitis B core antigen (anti-HBc), HBV DNA, and antibodies to the hepatitis C virus (anti-HCV). Anti-HCV positivity was significantly associated with a 12.6-fold increase in HCC risk (95% confidence limits = 4.7, 33.6). As expected, the presence of serum HBsAg and the presence of anti-HBc in the absence of anti-HBs were both positively associated with the risk of HCC. But most interestingly, among our study subjects, the presence of anti-HBs in the absence of HBsAg and HBV DNA (indicative of a resolved infection) was significantly related to a 4.7-fold increased risk for HCC (95% confidence limits = 2.2, 9.4). Overall, any serological evidence of prior HBV exposure was associated with a 9.4-fold elevation in HCC risk (95% confidence limits = 4.7, 18.7). The data also demonstrate a synergistic effect of HBV and HCV infections on the risk of HCC. We estimate that about 55% of HCC cases occurring in non-Asians of Los Angeles can be attributed to infection by the hepatitis B and/or C viruses.