Two different processes appear to be involved in the initiation of hepatocarcinogenesis by chronic hepatitis B virus (HBV) infection and by chronic hepatitis C virus (HCV) infection. Initiation of hepatocellular carcinoma (HCC) by chronic HBV infection usually occurs early in life; most patients have had onset of HBV infection before the end of childhood, although rare cases of HCC have been reported following HBV infections acquired in adulthood. In contrast, HCV-associated HCC in many cases probably develops after a chronic HCV infection that was acquired during adulthood. HBV-DNA usually is integrated in the tumor DNA of HBV-associated HCC; it produces two proteins that can transactivate known oncogenes in vitro and that theoretically could affect genes at distant sites in vivo. HCV is a nonintegrating virus and no transactivating HCV proteins have been identified so far. In the later stages of hepatocarcinogenesis, "tumor promotion" and "tumor progression," HBV-associated HCC may share certain features with those of HCV-associated HCC. Chronic inflammation and cirrhosis, accompanied by regenerative processes, may function as a tumor promoter, providing a common pathway from chronic HBV or HCV infection to HCC. Tumor progression may be brought about in HCC by mutations of the p53 tumor suppressor gene. Mutations of this gene are common in HCCs, and they are found more often in advanced human HCCs than in small, well-differentiated HCCs. The prevalences of p53 mutations are similar in HBV-associated and HCV-associated HCCs (30-50%). Even in the absence of a p53 mutation, the functions of normal p53 can be inactivated as a result of binding by viral or by cellular proteins. It is not known yet whether this type of binding contributes to the development of HCC, but p53 binding by the HBV X protein in vitro has been reported. Abnormalities of the RB tumor suppressor gene also have been found frequently in HCC patients, particularly in HCCs that contain p53 mutations.