BACKGROUND/AIMS: Transmission of hepatitis B virus (HBV) in countries of intermediate endemicity, such as Italy, is thought to be primarily horizontal and, to a lesser extent, vertical. Most chronic carriers therefore become infected in infancy or at a very young age. The index cases in such events have been assumed to come from within the family unit or from sources outside the immediate family, with whom the affected person is in close contact. METHODS: We studied a number of Italian families with multiple members chronically infected with HBV. The precore/core region of the virus was amplified from serum derived HBV-DNA, and the sequences subjected to phylogenetic tree analysis. In addition, the extent of amino-acid variation within the core region was correlated to HLA type, determined by allele-specific PCR. RESULTS: The phylogenetic tree analysis provided strong evidence of intra-familial transmission of the virus. Analysis of amino-acid substitutions in the core region in relation to HLA class II alleles from members of the same family showed that these substitutions were restricted in siblings with concordant, and more diverse in those with discordant HLA haplotypes. CONCLUSIONS: This is consistent with major histocompatibility complex class II mediated selection pressure on the virus.