Objective：To study the characteristics of HBV genotype/subgenotype and mutations in precore/core promoter（CP） region in chronic HBV-infected patients suffering from HBV clustering infection families with unfavorable prognosis and to analyze its cor－relation with the outcome of HBV infection. Methods：A total of 101 family clustering chronic HBV infected patients with unfavorable prognosis were enrolled in this study，including 31 cases of asymptomatic carriers（ASC），27 cases of chronic hepatitis B（CHB），13 cases of chronic severe hepatitis B（CSHB），30 cases of liver cirrhosis and/or hepatocellular carcinoma（LC/HCC） and 92 CHB pa－tients without family assemble features were taken as control group. HBV genotype/subgenotypes and mutations in precore/CP region of all samples were determined by nested-PCR combined with direct nucleotide sequence analysis. Results：Subgenotype Ba was pre－dominant in both experimental group and control group，followed by C2 and C1，only 1 subgenotype Bj was detected in experimental group. The prevalence of genotype C was dramatically higher and Ba was significant lower in experimental group than in control group（P<0.001）. In addition，patients infected with subgenotype C1 had higher prevalence of（LC/HCC） than patients infected with subgenotype Ba or C2（83.3% vs. 29.9%，11.8%，P<0.001）. There was no significant difference in the frequency of mutations in pre－core/CP region between the two groups. In experimental group，substitution mutations were detected at 17 sites，the variation rate in A1752，A1775，G1899 was not statistically different among ASC，CHB，CSHB and LC/HCC groups，while the prevalence of mutations in T1753，A1762，G1764，A1846，G1896 showed a trend of gradual increase along with diseases progression. In LC/HCC group，the frequencies of A1762T/G1764A double mutants and A1762T/G1764A/G1896A triple mutants were 73.3% and 36.7% respectively，obviously higher than those in ASC（22.6%，9.7%，P<0.01） and CHB group（29.6%，P<0.05）. Conclusions：The patients in ex－perimental group show dramatically increased prevalence of genotype C infection. Subgenotype C1 and multiple-site muta－tions in precore/CP region may be associated with the poor prognosis after HBV infection.