Recent studies have suggested that quantifying the serum HBsAg levels can predict the response to pegylated interferon. We aimed to determine the change in serum HBsAg levels during entecavir (ETV) treatment and the correlation with treatment response in chronic HBeAg-positive and HBeAg-negative hepatitis B patients. Serial HBsAg levels were measured using the Architect assay (Abbott Laboratories, Abbott Park, IL) in sera from 101 treatment-naive chronic hepatitis B (CHB) patients receiving ETV. During treatment, in HBeAg-positive patients, the mean HBsAg level was 3.51, 3.22, 3.34, 3.36, and 3.40 log10 IU/ml at baseline, 3, 6, 12, and 24 months, respectively, and there was no significant change compared with the baseline level, except the decline at 3 months (P = 0.009). In HBeAg-negative patients, the mean level of serum HBsAg showed increase with 3.06, 3.09, 3.20, 3.26, and 3.27 log10 IU/ml at baseline, 3, 6, 12, and 24 months of treatment, respectively. In HBeAg-positive patients, HBV-DNA negativity (<2,000 copies/ml; P = 0.010) and HBsAg level <3,000 IU/ml (P = 0.026) at 3 months were independent predictors of HBeAg loss/seroconversion at 12 months. After 24 months of treatment, the HBsAg levels at baseline (P = 0.046) was an independent factor of HBeAg loss/seroconversion. In HBeAg-negative patients, undetectable HBV DNA at 6 months was an independent factor predicting undetectable HBV DNA after 12 months of therapy. The level of serum HBsAg before and during therapy was a good predictor of HBeAg loss/seroconversion in naïve HBeAg-positive CHB patients receiving entecavir. J. Med. Virol. 83:1178–1186, 2011. © 2011 Wiley-Liss, Inc.