In the Mediterranean region almost all patients with hepatitis B virus (HBV)-related cirrhosis are anti-HBV e antigen (anti-HBeAg)-positive and carriers of HBeAg-negative virus mutants. The six members of a family who acquired HBV infection were recently studied: two siblings developed cirrhosis with persistence of HBeAg positivity, whereas their parents and two more siblings cleared the virus. The two cirrhotic patients showed homozygosity for HLA class I by phenotype, which is a rare occurrence in the general population, while the other family members were heterozygous for HLA class I. The sequencing analyses of the entire viral DNAs isolated from both cirrhotic patients showed that the two viral genomes were almost identical and no mutation preventing HbeAg synthesis or viral gene expression was present. These findings might suggest that homozygosity for HLA class I molecules might be responsible for an insufficient response to the virus, favouring chronic outcome of the infection and the long-lasting persistence of HBV populations that produce HBeAg.