Polymorphisms in estrogen receptor alpha (ESR1) are reported to be associated with the susceptibility to persistent HBV infection, HBV liver cirrhosis and HBV-related hepatocellular carcinoma (HCC).To test the hypothesis that polymorphisms in estrogen receptor alpha (ESR1) might influence the virological response to entecavir (ETV) therapy, we examined two polymorphisms (PvuII and XbaI) in 76 nucleoside-naïve chronic hepatitis B (CHB) patients. All of the patients (52 HBeAg-positive and 24 HBeAg-negative) were treated with ETV 0.5 mg daily and followed up for a median time of 96 weeks (range 48-96). Polymorphisms were determined using the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method.Under an additive model, the univariate analysis showed that patients carrying the PvuII T/C genotype might have higher virological responders than those carrying the T/T and C/C genotypes at week 48 (87.7 vs. 57.1 vs. 58.3 %; P = 0.012) and week 96 (96.7 vs. 64.3 vs. 24 87.5 %; P = 0.018), although this difference disappeared with the multiple analysis at week 48 [95 % confidence interval (CI) 0.687-3.841; P = 0.269] and week 96 (95 % CI 0.861-18.016; P = 0.077). Conversely, the univariate analysis suggests statistical significance between the recessive model of PvuII (TT vs. TC/CC) and virological response at week 48 (57.1 vs. 81.1 %; P = 0.033) and week 96 (64.3 vs. 94.7 %; P = 0.017). Multiple regression analysis affirmed the significant and independent association between the recessive model of PvuII and virological response. In other words, patients carrying at least one PvuII C allele (TC/CC) had a better likelihood of achieving virological response compared with those carrying the T/T genotype at week 48 (95 % CI 1.026-14.785, P = 0.046) and week 96 (95 % CI 1.456-57.509; P = 0.018). XbaI polymorphisms were not significantly associated with virological response.Our results suggest that the PvuII polymorphism may play an important role in determining ETV efficacy after 48 and 96 weeks of treatment, at least in this study population.