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Background: We aimed to investigate the characteristics of hepatitis B virus (HBV) genotype C subgroups in Hong Kong and their relationship with HBV genotype C in other parts of Asia., Methods: Full-genome nucleotide sequences of 49 HBV genotype C isolates from Chinese patients with chronic hepatitis B were compared with the sequences of 69 HBV genotype C isolates and 12 non-genotype C isolates in the GenBank database. Phylogenetic analysis was performed to define the subgroups of HBV genotype C on the basis of >4% heterogeneity of the entire HBV genome., Results: HBV in 80% of patients in Hong Kong belonged to a subgroup predominantly found in Southeast Asia (Vietnam, Thailand, Myanmar, and southern China) designated as HBV genotype "Cs," and HBV in the remaining 20% of patients belonged to another subgroup, predominantly found in the Far East (Korea, Japan, and northern China), designated as HBV genotype "Ce." Overall, the mean+/-SD nucleotide sequence difference between HBV genotype Cs and HBV genotype Ce was 4.2%+/-0.3%. When HBV genotype Cs and HBV genotype Ce were compared among patients in Hong Kong, HBV genotype Cs was associated with a higher tendency to develop basal core promoter mutations (80% vs. 50%; P=.14), a higher prevalence of C at nucleotide 1858 (95% vs. 0%; P<.001), and a lower prevalence of precore stop codon mutations (5% vs. 50%; P=.002)., Conclusions: HBV genotype C can be differentiated into 2 subgroups--namely, genotype Ce and genotype Cs--that have different epidemiological distributions and virological characteristics.