In Asia, genotypes B and C are the most common genotypes of hepatitis B virus (HBV); and genotype C causes more severe liver disease. Core promoter/precore (CP/PC) mutants, known to be linked to these genotypes, could have an impact on the progression and severity of liver disease. Sera of 115 patients, including 39 acute and 76 chronic Vietnamese HBV infected patients, were tested for their liver profile, HBeAg, HBV genotypes, and HBV DNA level. Fragments of 282 nucleotides covering CP/PC were amplified, sequenced, and analysed. In the acute group, CP/PC mutants accounted for 38.4 and 25.6%, respectively. Genotype B was found to be predominant (74.3%, P < 0.05) and linked to the PC mutant (A1896) (P < 0.05). In the chronic group, CP/PC mutants accounted for 61.7 and 32.8%. CP mutants, especially the T1762/A1764 double mutant, were found to correlate with genotype C (81%, P < 0.001), liver cirrhosis, and hepatocellular carcinoma (P < 0.05). Therefore, genotype C in Vietnam, which carried high rate of C-1858 (70%), could play an important role in causing severe chronic liver disease. J. Med. Virol. 74:228–236, 2004. © 2004 Wiley-Liss, Inc.