The precore stop-codon variant of hepatitis B virus (HBV) has been implicated in fulminant hepatitis. The precore/core regions of such variants from two sets of patients with interpartner transmission resulting in fulminant hepatitis in the contact, were sequenced to establish whether further sequence variations in the core region are specifically associated with the fulminant disease. In both sets of patients, there was sequence diversity of the precore/core region from the wild type, leading to numerous amino acid substitutions in the core region. Between the infecting source and the contact, there was only one amino acid change in one set of patients and none in the other. In addition, in the second set of patients, serum samples from four different time points were investigated. Sequence data showed no variation in each patient at the nucleotide level in the core region, even in the case of the source, who was followed for 3 years. In this same pair of subjects, the remainder of the genome was sequenced and was identical at the nucleotide level. Therefore, it appears that, at least in some cases of fulminant hepatitis caused by infection with the precore variant, the nucleotide sequence of the patient with fulminant hepatitis is identical to that observed in the asymptomatic source of infection. These data indicate that the severity and outcome of infection in such cases are unrelated to any additional variation in the entire HBV genome, and that the changed clinical picture is dependent on host factors, possibly the HLA environment. HLA typing of both the contact and source in the two sets of patients revealed that the contacts with fulminant hepatitis had one or more alleles at the HLA class II locus, previously shown to be associated with an acute hepatitis sufficient to clear the virus.