Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Saharan Africa where the major risk factors are chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins. Aflatoxin B1, the most commonly occurring and potent of the aflatoxins is associated with a specific AGG to AGT transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease. Prospective epidemiological studies have shown a more than multiplicative interaction between HBV and aflatoxins in terms of HCC risk. However, the biology underlying this statistical interaction is not fully understood. There are a number of potential mechanisms including, among others: the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection; the predisposition of HBV-infected hepatocytes to aflatoxin-induced DNA damage; an increase in susceptibility to chronic HBV infection in aflatoxin-exposed individuals; and oxidative stress exacerbated by co-exposure to aflatoxins and chronic hepatitis infection. Priorities for prevention are global HBV vaccination, primary and secondary prevention strategies against aflatoxin and the avoidance of transmission of HCV through good hygiene practices.