Precore hepatitis B virus mutants have been detected mainly in HBeAg-negative patients with active liver disease. We previously reported two novel mutations: M, (C-to-T change at nucleotide 1856 [proser at codon 151) and M, (G-to-A change at nucleotide 1898 [gly-ser at codon 291) in addition to two welldescribed mutations: Ma (G-to-A change at nucleotide 1896 [trp-stop at codon 281); and M, (G-to-A change at nucleotide 1899 [gly-asp at codon 291) in Chinese patients. The aims of this study were to determine (a) the prevalence of precore HBV mutations in asymptomatic carriers and (b) whether family members share the same mutated sequence as the indexpatients. Fifty-three index patients and 89 HBsAg-positive family members were studied by means of direct sequencing of polymerase chain reaction-amplified hepatitis B virus DNA. M,,, a conserved mutation (T-to-C at nucleotide 1858, codon 151, was detected in 81% and 12% family members of index patients with and without M , , respectively (p < 0.0001). The clustering of M, indicates that most subjects were infected through intrafamilial transmission. MI was detected in all the family members of patients with M, but in none of the family members of patients with wild-type or M, sequences (p < 0.0001). M, was detected in 25%, 0% and 15% of family members of patients with M,, M, and WT sequences, respectively (p = 0.19). M, was detected in five and M, in four family members. M, was equally distributed among HBeAg-positive and HBeAg-negative family members, 19.6% vs. 9% (p = 0.34). whereas M, was detected more frequently in HBeAg-negative family members: 45.5% vs. 4.5% in HBeAg-positive family members (p c 0.0001). Ten (77%) of 13 family members with M, and all 15 family members with M, had normal serum aminotransferase levels. The family members with M, were significantly older than those with wild-type or MI sequences (mean ages, respectively, 37.9 f 5,23 f 1.4 and 24.1 f 3 yr; p = 0.0005). In addition, M, was more frequently detected in family members who were older than the index patients. Longitudinal studies documented progression from