To investigate the effect of hepatitis delta virus (HDV) superinfection on the long-term outcome of Japanese subjects with chronic hepatitis B virus (HBV) infection, we examined the presence of antibodies to hepatitis delta antigen (anti-HD) in serial serum samples collected from 1127 subjects with chronic HBV infection. The subjects were followed for at least 36 months (mean: 121.3 months) between 1973 and 1991. Among 69 cases where anti-HD was detected, eight (12%) developed liver cirrhosis (LC) and six (9%) developed hepatocellular carcinoma (HCC). However, among 1058 cases without anti-HD, there were 43 patients (4%) who developed LC and 29 (3%) who developed HCC. The prevalence of LC and HCC was significantly higher among the cases with anti-HD than those without anti-HD. The proportion of LC and HCC per 1000 person years was 10.46 and 7.84, respectively among cases with anti-HD, and 4.05 and 2.73 among those without anti-HD, respectively. The overall relative risk of LC and HCC was 2.58 and 2.87, respectively; 95% confidence interval (CI): LC, 1.14-5.13; HCC, 1.03-6.23. These results indicate that in the Kure district in Japan, where HDV infection of persons infected with HBV is about 6%, such superinfection increases the risk of LC and HCC.