The genotype-related differences between genotype C and genotype D of the hepatitis B virus (HBV) remain unknown. The relationship was studied between the HBV genotypes and their clinical features, paying special attention to genotypes C and D. Serum samples from 413 HBV carriers were genotyped using an enzyme immunoassay (EIA) and by restriction fragment length polymorphism. The nucleotide sequences at the basic core promoter (BCP) and precore (PreC) regions were analysed by direct sequencing. The full genome sequences of three HBV genotype D cases were also examined. Almost all carriers with HBV genotype D were asymptomatic carriers (84.2%). Genotype D was not found in patients with liver cirrhosis and hepatocellular carcinoma. In contrast, carriers with genotype C had mainly chronic liver disease (63.2%; P < 0.001). The ratio of hepatitis B e antigen (HBeAg)/anti-HBe was significantly higher in genotype C than in genotype D in the young age-matched group (P < 0.01). The mutation at BCP (T1762, A1764) was significantly lower in genotype D than in genotype C among HBeAg-negative patients (P < 0.05). The HBV full-genome sequences are very similar to certain HBV genotype D sequences from Europe. In conclusion, genotype C was associated with chronic liver disease, whereas genotype D was related to asymptomatic carriers with earlier HBeAg seroconversion. Thus, the outcome of chronic HBV infection may be different in persons infected with HBV genotypes C and D. J. Med. Virol. 72:551–557, 2004. © 2004 Wiley-Liss, Inc.