We made a prospective study on the development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis with hepatitis B virus infection from April, 1973 to December, 1977. Seven out of 30 patients (23%) with hepatitis B surface antigen (HBsAg)-positive cirrhosis developed HCC. On the other hand, only 5.9% of the patients with HBsAg-negative liver cirrhosis developed HCC. These patients were classified into three groups according to their anti-HB core (anti-HBc) titers. When the anti-HBc titer, expressed as a dilution of serum, was 210 or more (Group I),20-24 % of the liver cirrhosis patients developed HCC either with or without a detectable amount of HBs Ag present in the sera. When the anti-HBc titer was 29 or less (Group II), only 0–5.7% developed HCC. There was no significant difference between this and the anti-HBc and HBsAg-negative group (Group III), which was 4.4%. In five individual cases from group I, HBsAg was detected in serum, and in biopsies of liver cells, before HCC could be detected by angiography and/or rising levels of alphafetoprotein (AFP).In all of these cases, the anti-HBc titer was higher than 210 throughout the observation period, even before the development of HCC. These findings indicate that active virus proliferation in chronic hepatitis B virus infection precedes the development of HCC as indicated by a higher anti-HBc titer. Therefore we have prepared these studies to show the pathogenic role of hepatitis B virus in the development of hepatocellular carcinoma.