BACKGROUND: Much evidence demonstrates that the genotypes of hepatitis B virus (HBV) present differences in pathogenicity and outcomes owing to differences in genetic structure. This study aimed to investigate the inlfuences of HBV genotypes on the anti-viral therapeutic efifcacy of interferon-α (IFN-α) in chronic hepatitis B patients, and to determine the relationship between HBV genotypes and levels of viral replication or gene variations. METHODS: The chronic hepatitis B patients who were treated with IFN-α were selected randomly. Anti-viral therapeutic efifcacy was monitored in these patients. The HBV genotypes were detected by PCR microplate hybridization ELISA. The levels of serum HBV-DNA were determined by lfuorescence quantitative PCR. HBV gene variation at pre-C and basic core promoter (BCP) regions were assayed by gene chip technology. RESULTS: Genotypes B and C were predominant in 94 chronic hepatitis B patients. A, E and F genotypes were not found in these patients. The HBV-DNA levels of genotype C and mixed genotypes were signiifcantly higher than those of genotype B. The response to IFN-α in patients with genotype B was markedly better than in those with genotypes C and D, and the complete response to IFN-αwas only observed in genotype B. The response to IFN-αin patients with mixed genotypes was the least sensitive. The negative transition of HBeAg was correlated with variations in the HBV pre-C and BCP regions in patientswith partial or no response to IFN-α. The variation rates of HBV pre-C and BCP regions were clearly higher in genotype C than in genotype B. CONCLUSIONS:The results suggest that HBV genotype is correlated with the serum levels of HBV-DNA, HBV gene variations and therapeutic efifcacy of IFN-α. The regular detection of HBV genotypes in the clinic will be of beneift for disease prognosis and planning of anti-viral therapeutic strategies.