Hepatocellular carcinoma (HCC) is the most frequent cancer of the liver and, worldwide, is the seventh most common tumor in males and the ninth in females; the annual incidence is estimated to be 1,000,000 cases newly diagnosed, with a male to female ratio of 4:1. The incidence of HCC is Italy is 6.9 cases for males and 2.7 for females as for the regions with intermediate risk for this tumor. During the last ten years many epidemiological studies, case-control and cohort, have associated HCC to hepatitis B virus (HBV) infection establishing that among HBsAg carriers the relative risk of HCC is between 10 and 20 to demonstrate the strength of the association. In addition to HBV infection, cirrhosis, aflatoxins, alcohol, tobacco smoking and oral contraceptives have been evaluated as risk factors for HCC. The importance of the contribution of these risk factors to the development of HCC and the perspectives for prevention in different geographical areas will be discussed.