Precore mutants of hepatitis B virus (HBV) were looked for in 18 hepatitis B e antigen (HBeAg) carriers who were treated with recombinant interferon-alpha (rIFN) and the results were compared with those obtained in 12 untreated carriers who underwent spontaneous HBeAb seroconversion. Molecular analysis of the HBV precore region was carried out by polymerase chain reaction (PCR) amplification and direct sequencing. Precore mutants with a stop codon at codon 28 were detectable at baseline in 19/30 carriers. However, wild-type strains predominated in the baseline sera of both treated (n = 16) and untreated (n = 10) patients. Sera from the remaining four patients contained predominantly or exclusively mutant virions. Following IFN treatment, there was a shift from the wild-type pattern to the mutant pattern in all patients, with the precore pattern prevailing in long-term responders (six out of nine) compared with the non-responders (none of nine). The wild-type pattern predominated among the non-responders (eight vs three), suggesting that the long-term response to IFN was associated with take-over of precore mutants. There were no relationships between any pretreatment precore molecular pattern and disease severity or outcome of treatment. Precore mutants also took over in 10 of the 12 untreated patients (83%), who underwent spontaneous HBeAb seroconversion. Thus, a shift from wild-type to precore mutant pattern occurs in most Italian patients undergoing IFN-induced or spontaneous HBeAb seroconversion.