Liver diseases associated with chronic hepatitis B virus (HBV) infection, including hepatocellular carcinoma, account for more than 1 million deaths annually worldwide. In addition to HBV infection, other risk factors are involved in the etiology of hepatocellular carcinoma and, among these, dietary exposure to the carcinogenic aflatoxins is of particular importance in certain regions of southeast Asia and sub-Saharan Africa. The relative contributions of these two risk factors and the mechanism of the interaction between them in the pathogenesis of hepatocellular carcinoma are still poorly understood. The recently developed individual biochemical and molecular markers of aflatoxin exposure, i.e., aflatoxin-albumin adducts in blood and a specific GC to TA transversion mutation in codon 249 of the p53 gene (249ser p53 mutation) in hepatocellular carcinomas, permit a better quantitative estimation of aflatoxin exposure in different populations of the world. A comprehensive summary of the data from our laboratory and the literature, based on a large number (>1000) of individual cases of hepatocellular carcinoma, is presented here and shows the following: 1) A high level and high prevalence of exposure to aflatoxins occur in West Africa, Mozambique, and some regions of China; 2) a high prevalence of the 249ser p53 mutation is detected in these countries; and 3) hepatocellular carcinomas from countries with low or no exposure to aflatoxins show a very low prevalence of the 249ser p53 mutation and distinctly different p53 mutation spectra, probably indicating different etiologies. Experimental and epidemiologic studies demonstrate an interaction between HBV infection and aflatoxins in hepatocarcinogenesis. The relevance of the biochemical/molecular markers of aflatoxin exposure, HBV vaccination, and the reduction of aflatoxin exposure, in addition to the interaction between HBV infection and other risk factors in liver carcinogenesis, are discussed with regard to the implementation of measures for primary prevention.