The sequence in the precore and core region of the hepatitis B virus (HBV) genome in the serum of five chronic active hepatitis patients at four different stages in each individual were studied by polymerase chain reaction and DNA sequencing to determine the prevalence and type of precore and core mutants in each chronic active hepatitis (CAH) patient. Gradual changes of the virus genome in each CAH patient in precore and core regions were identified. Except for the virus from one patient, the mutant viruses showed gradual changes of genome sequences, which resulted in the generation of stop codons at the precore and core region, causing the association of active hepatitis in each patient even in the presence of anti-HBe. Mutational hot spots in the core region, which includes a clustering of changes in a small region of 14 amino acids (codons 84-97 from the start of the core gene) were found in all patients. This region of mutational hot spots in the core might be a major target of cytotoxic T lymphocytes (CTL), which has evolved under the pressure of immune selections, and these mutants might play a important role in the pathogenesis of viral hepatitis.