Objective To explore the predictive value of baseline HBsAg level and early response for HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment. Methods A total of 121 patients with HBeAg-positive chronic hepatitis B who achieved HBsAg loss were enrolled; all patients were treated with PEG-IFNα-2a 180 μg/week. Serum HBV DNA and serological indicators(HBsAg, anti-HBs, HBeAg, and anti-HBe) were determined before and every 3 months during treatment. Results The median treatment time for HBsAg loss was 84 weeks(7-273 weeks), and 74.38%(90 cases) of the patients needed extended treatment(> 48 weeks). The correlation between baseline HBsAg levels and the treatment time of HBsAg loss was significant(B = 14.465, t = 2.342, P = 0.021). Baseline HBsAg levels together with the decline range of HBsAg at 24 weeks significantly correlated with the treatment time of HBsAg loss(B = 29.862, t = 4.890, P = 0.000 and B = 27.993, t = 27.993, P = 0.005). Conclusion Baseline HBsAg levels and extended therapy are critical steps toward HBsAg loss. Baseline HBsAg levels together with early response determined the treatment time of HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment. Objective To explore the predictive value of baseline HBsAg level and early response for HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment. Methods A total of 121 patients with HBeAg-positive chronic hepatitis B who achieved HBsAg loss were enrolled; all patients were treated with PEG-IFNα-2a 180 μg / week. Serum HBV DNA and serological indicators (HBsAg, anti-HBs, HBeAg, and anti-HBe) were determined before and every 3 months during treatment. median treatment time for HBsAg loss was 84 weeks (7-273 weeks), and 74.38% (90 cases) of the patients needed extended treatment (> 48 weeks). The correlation between baseline HBsAg levels and the treatment time of HBsAg loss was significant (B = 14.465, t = 2.342, P = 0.021). Baseline HBsAg levels together with the decline range of HBsAg at 24 weeks were statistically correlated with the treatment time of HBsAg loss (B = 29.862, t = 4.890, P = 0.000 and B = 27.993, t = 27.993, P = 0.0 Baseline HBsAg levels together with early response determined the treatment time of HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment.