Background: This study aimed to evaluate the predictive values of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) levels in 171 Chinese patients with chronic hepatitis B who received a 48-week course of pegylated interferon alfa-2b therapy at 1.5 mcg/kg. Methods: HBsAg, HBeAg, and hepatitis B virus (HBV) DNA levels were measured at baseline and weeks 12, 24, 48, and 72. Clinical responses were defined as a combined response (CR, HBeAg seroconversion [ sustained response, SR] combined with HBV DNA level < 2,000 IU/mL at week 72). The positive predictive value and negative predictive value were calculated for HBsAg alone and/or combined with HBeAg and HBV DNA at weeks 12 and 24. Results: Of 171 patients included, 58 (33.9 %) achieved a SR. Of patients who achieved a SR, 33 (56.9 %) achieved a CR. Totally 19.3 % (33/171) patients achieved CR and 80.7 % (138/171) patients did not. Patients with HBsAg < 1500 IU/mL at week 12 had a 47.4 % chance of achieving an off-treatment SR and patients with a HBsAg decrease > 1.5 logIU/mL at week 12 had a 54.5 % chance. Patients with HBsAg > 20,000 IU/mL at weeks 12 and 24 had a 93.8 and 100.0 % chance, respectively, of not achieving a CR. An HBsAg level or changes at weeks 12 and 24, combined with HBeAg or HBV DNA, increased the chance for a SR and CR. Conclusions: On-treatment HBsAg quantification, alone or in combination with HBeAg or HBV DNA, predicted off-treatment SR and CR after 48 weeks of PEG-IFNa-2b therapy, and thus, may guide clinicians in making a therapeutic decision to continue or terminate the therapy.