Heavy alcohol consumption, chronic infection with the hepatitis B virus (HBV) or the hepatitis C virus (HCV), tobacco smoking, and diabetes are risk factors for hepatocellular carcinoma (HCC). In the Los Angeles Non-Asian HCC Study, heavy alcohol intake was shown to exhibit synergistic effects with viral hepatitis (HBV, HCV) and diabetes in the causation of HCC among individuals with joint exposures. Although chronic infection with HBV is recognized as the most important causal factor for HCC in humans, only a minority of HBV carriers eventually develop HCC, suggesting the presence of important cofactors in HBV-related HCC. In the Guangxi/China HCC Study, a 20-fold difference in HCC risk was observed between individuals possessing the least versus the most favorable cytokine genotypes for hepatitis B viral clearance. Experimental studies have indicated an important role for one-carbon metabolism in HCC development. In both the Los Angeles and Guangxi studies, low-activity genotypes (reduced enzymatic activities) of methylenetetrahydrofolate reductase (MTHFR) and high-activity genotypes (enhanced enzymatic activities) of thymidylate synthase (TYMS), both of which discourage the misincorporation of uracil into DNA, were shown to be associated with a reduced risk for HCC.