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The role of quantitative hepatitis B surface antigen (HBsAg) levels in patients receiving oral antiviral therapy is controversial. We aimed to determine the HBsAg response in chronic hepatitis B patients treated with entecavir 0.5 mg daily for 2 years.A total of 166 patients were included. Liver biochemistry, hepatitis B virus (HBV) serological markers, HBV DNA, and quantitative HBsAg levels were performed at baseline, year 1, and year 2 after commencing entecavir. Additional HBsAg levels were measured at 12 and 24 weeks in patients with available sera.In all, 68 patients were hepatitis B e-antigen (HBeAg) positive. Age, HBV DNA, and alanine aminotransferase (ALT) were significantly correlated with HBsAg levels at baseline (r=−0.429, 0.607, and 0.254, respectively, allP<0.05). The correlation with HBV DNA and ALT levels was reduced by entecavir treatment, and was lost after 2 years of treatment. There was an overall decline in HBsAg levels from baseline to year 1 to year 2 (3,377.4 vs. 2,316.5 vs. 1,903.0 IU/ml, respectively,P<0.001). However, at year 2, 102 patients (61%) had no significant changes (<0.5 log difference), 50 (30%) had significant decline (≥0.5 log decrease), whereas 14 (9%) had significant increase (≥0.5 log increase). Of the patients, 151 (91%) had undetectable HBV DNA; 25 (37%) underwent HBeAg seroconversion. Neither HBsAg at baseline nor early decline at weeks 12 or 24 was predictive of HBeAg seroconversion at 2 years.Despite HBV DNA suppression, the majority did not show significant decline in HBsAg levels. Early decline of HBsAg levels at 12/24 weeks was not associated with HBV DNA suppression or HBeAg seroconversion.