Although infection with hepatitis C virus (HCV) has become a leading cause of hepatocellular carcinoma, the mechanisms by which it results in carcinogenesis remain a subject of debate. Here, we explore the possibility that HCV replication impairs cellular DNA damage responses, thereby promoting instability of the infected host cell genome, and that HCV exerts a direct cancer-promoting effect in addition to eliciting immune-mediated inflammation and apoptosis of hepatocytes contributing to hepatocellular carcinogenesis.