Persistent infection with hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC). However, it remains controversial in the pathogenesis of HCC associated with HCV as to whether the virus plays a direct or an indirect role. The studies using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation would also play a role. The downstream events of the core protein are segregated into two components. One is the augmented production of oxidative stress along with the activation of scavenging system, including catalase and glutathione, in the putative pre-neoplastic stage with steatosis in the liver. Thus, oxidative stress production in the absence of inflammation by the core protein would partly contribute to the development of HCC. The generation of oxidative stress is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other component is the alteration of intracellular signaling cascade of mitogen-activated protein kinase and activating factor (AP)-1, leading to the activation of cell cycle control. The combination of these pathways, collective with HCV-associated alterations in lipid and glucose metabolism, would lead to the frequent development of HCC in persistent HCV infection. These results suggest that there would be a mechanism for hepatocarcinogenesis in persistent HCV infection that is distinct from those for the other cancers. Similar to the pathogenesis of other cancers, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore unlike for other cancers, HCV infection may be able to cause HCC in the absence of a complete set of genetic aberrations. Such a scenario, 'non-Vogelstein-type' carcinogenesis, would explain the rare feature of hepatocarcinogenesis in HCV infection, the extraordinarily high incidence and the multicentric nature of HCC development.