There has been a rapid increase in the number of patients with hepatocellular carcinoma (HCC) in Japan. This may be the result of an increased number of patients with hepatitis C virus (HCV)-related liver disease, and of prolonged survival of these patients due to improvement in the management of cirrhosis. Indeed, 96% of recent HCC patients admitted to our hospital were related to viral hepatitis B or C, and HCV infection accounted for three-fourths of these cases. Since most HCCs develop in the course of chronic liver disease, it is important to identify high risk groups for HCC development and to detect small HCCs early. We have established a screening method by combining various imaging studies and the measurement of serum alpha-fetoprotein; this combination has markedly increased the detection of small HCCs less than 2 cm in diameter. Multiple HCCs can occur in the same patient, either simultaneously or successively. Partly for this reason, the cumulative recurrence rate of HCC is very high even after surgical resection. In order to determine whether such HCCs arise from the common or different clonal origins, we have utilized the restriction landmark genomic scanning method. It remains to be clarified whether HCV plays a direct role in hepatocarcinogenesis, and whether antiviral treatments such as interferon eventually will decrease the incidence of HCC among patients with chronic HCV infection.