In Japan, hepatocellular carcinoma (HCC) is the fourth leading cause of death in males and the fifth in females. Hepatitis C virus (HCV) is a major cause of HCC in Japan, with 70% of cases being HCV related. HCV genotype 1b, the most prevalent subtype in Japan, started to spread in the 1930s among injecting drug users (IDUs) during and after World War II or through medical procedures such as blood transfusion and use of contaminated syringes. The prevalence of HCV infection is much lower in the current younger generation compared with that in the older generation, particularly those aged >55 years (0.1–0.2% vs. ≧ 2%). Therefore, the total number of patients with HCV infection is estimated to decrease, even though sporadic HCV transmission is mainly seen among young IDUs. Of note, HCV genotype 2 seems to be spreading among IDUs, but the response to antiviral therapy in these patients seems to be better than that in older patients, irrespective of the genotype. Although the number of patients who die because of HCC has steadily increased over the last 50 years, the incidence of HCC is now decreasing, mainly because of the decreased prevalence of HCV-related HCC.