Persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). One of the characteristics of HCV infection is the unusual augmentation of oxidative stress, which is exacerbated by iron accumulation in the liver, as observed frequently in hepatitis C patients. Using a transgenic mouse model, in which HCC develops late in life after the preneoplastic steatosis stage, the core protein of HCV was shown to induce the overproduction of reactive oxygen species (ROS) in the liver. In excessive generation of ROS, HCV affects the steady-state levels of a mitochondrial protein chaperone, i.e. prohibitin, leading to an impaired function of the mitochondrial respiratory chain with the overproduction of ROS. Insulin resistance and hepatic steatosis, which frequently accompany HCV infection, exacerbate ROS production. On the other hand, HCV compromises some of the antioxidant systems, including heme oxygenase-1 and NADH dehydrogenase quinone 1, resulting in the provocation of oxidative stress, together with ROS overproduction, in the liver with HCV infection. Thus, HCV infection not only induces ROS but also hampers the antioxidant system in the liver, thereby exacerbating oxidative stress that would facilitate hepatocarcinogenesis. Combination with the other activated pathway, including an alteration in the intracellular signaling cascade of MAP kinase, along with HCV-associated disturbances in lipid and glucose metabolism would lead to the unusual mode of hepatocarcinogenesis, i.e. very frequent and multicentric development of HCC, in persistent HCV infection.