OBJECTIVE: To investigate the association of hot-spot mutations in hepatitis B virus (HBV) pre-C region with the occurrence and outcome of severe hepatitis B. METHODS: A total of 68 patients with severe hepatitis B negative for hepatits B e antigen (HBeAg) were enrolled in this study, including 6 cases of acute, 38 cases of subacute and 24 chronic severe hepatitis B, with another 44 HBeAg-positive patients with chronic hepatitis B serving as control. Mismatch PCR and restriction fragment length polymorphism analysis were employed to examine the mutations of T1862 and A1896 in this 2 groups of patients. RESULTS: The mutation rates at A1896 and T1862 were 66.7% (4/6) and 0 (0/6) respectively in acute severe hepatitis B cases, 42.1% (16/38) and 15.8% (6/38) in subacute severe hepatitis, 25.0% (6/24) and 16.7% (4/24) in chronic severe hepatitis, and 45.5% (20/24) and 2.3% (1/44) in chronic hepatitis cases. There were significant differences in terms of T1862 mutation between patients with severe hepatitis and chronic hepatitis (P<0.01). CONCLUSION: T1862 mutation is closely related to the exacerbation of chronic hepatitis, while the role of A1896 mutation in this process requires further investigation.