To investigate the relationship of the HBV preC/C gene mutations with the disease persistence and exacerbation, the sequence of this region was analysed with direct sequencing by using the polymerase chain reaction product of the DNAs extracted from 24 such cases. A mutant with preC stop codon at the site 28 was detected in all the 11 anti-HBe-positive patients with different severity. This stop 28 mutant also coexisted with wild virus in seven of 18 HBeAg-positive patients. C gene mutations clustered in a small segment of codon 84-101, of those especially codon 97 was substituted in 11 of 15 mutants. There were 2, 6 and 20 codon mutations in 8 mild, 6 moderate and 10 severe cases respectively. In addition, the deletion of 144bp was also found in this region in a moderate case and that of 96bp in a severe case. Follow up of six patients revealed a close correlation between increase of genetic variation and advance of pathology.