Persistent infection with hepatitis C virus (HCV) is a major risk toward development of hepatocellular carcinoma (HCC). However, it remains controversial in the pathogenesis of HCC associated with HCV whether the virus plays a direct or an indirect role. The observation that chronic hepatitis C patients with sustained high levels of serum alanine aminotransferase are prone to develop HCC suggests the significance of inflammation in hepatocarcinogenesis in hepatitis C. However, the rare development of HCC in patients with autoimmune hepatitis, which is accompanied by robust inflammation, even after the progress into cirrhosis, implies a possibility of the direct role of HCV in HCC development. What is the role of HCV, a simple plus-stranded RNA virus, whose genome is never integrated into the host genome, in hepatocarcinogenesis? The studies using transgenic mouse and cultured cell models, in which the HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activities. In particular, the core protein of HCV induces overproduction of oxidative stress by impairing the mitochondrial electron transfer system, through insulting the function of molecular chaperon, prohibitin. HCV also modulates the intracellular signaling pathways including mitogen-activated protein kinase, leading to the acquisition of growth advantage by hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolisms, thereby accelerating the progression of liver fibrosis and HCC development. These results would provide a clue for further understanding of the role of HCV in pathogenesis of persistent HCV infection including hepatocarcinogenesis.