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Background The aim of this study was to assess the influence of hepatitis B virus (HBV) genotypes on serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative patients treated with pegylated interferon-a2a (PEG-IFN-a2a).Methods A total of 48 consecutive patients treated with PEG-IFN-a2a (180 µg/week) for 48 weeks were assessed. HBV genotype was determined. Serum HBV DNA and HBsAg were assessed at baseline, during treatment (weeks 12, 24 and 48) and during follow-up (weeks 72 and 96).Results The distribution of HBV genotype was A 27%, B 17%, C 12%, D 29% and E 14%. Mean ±sdpretreatment serum HBV DNA (6.9 ±1.5 log10copies/ml) was not different between genotypes and decreased under treatment in all genotypes without significant difference. Mean ±sdpretreatment serum HBsAg (3.6 ±0.6 log10 IU/ml) was significantly different between genotypes (P<0.001), with high levels in genotypes A and C, intermediate levels in genotypes D and E, and low levels in genotype B (4.0 ±0.3, 4.1 ±0.7, 3.6 ±0.5, 3.6 ±0.4 and 2.7 ±0.6 log10IU/ml, respectively). Serum HBsAg decreased under treatment in all genotypes with a significant difference. At the end of treatment, mean ±sddecrease was high in genotype A, intermediate in genotypes B and D, and low in genotypes C and E (1.3 ±1.6, 0.7 ±0.7, 0.6 ±0.9, 0.4 ±1.0 and 0.4 ±0.9 log10IU/ml, respectively; P<0.001). During follow-up, serum HBsAg continued to decrease in genotypes A and D, whereas rebound was observed in genotypes B, C and E.Conclusions HBV genotype has a strong influence on serum HBsAg kinetics during PEG-IFN-a2a therapy in HBeAg-negative patients.