Background & Aims: Response-guided therapy has been confirmed to be an effective strategy for the treatment of chronic hepatitis C in the pegylated interferon (PegIFN) era, but no randomized trial utilizing this strategy has been conducted in chronic hepatitis B. Methods: In this open-label, multicenter, randomized trial, HBeAg positive patients were treated with PegIFN (180 mu g/week) for 24 weeks. Early responders (HBsAg <1500 IU/ml and HBV DNA <10(5) copies/ml at week 24) received PegIFN for a further 24 weeks (arm A), while non-early responders were randomized to PegIFN for another 24 weeks (arm B), another 72 weeks (arm C) or PegIFN for another 72 weeks plus adefovir for 36 weeks (arm D). The primary endpoint was the change of quantitative HBsAg from baseline to the end of follow-up (EOF). Results: For non-early responders, 96-week PegIFN monotherapy did not lead to a greater reduction of HBsAg from baseline to EOF, compared with 48-week PegIFN (-0.71 vs. -0.67 log(10)IU/ml, P = 0.407). The rate of HBeAg seroconversion with HBV DNA <2000 IU/ml at EOF were similar for arms B, C and D (17.9%, 23.9% and 25.0% respectively). For patients with HBsAg <1500 IU/ml or HBV DNA <10(5) copies/ml at week 24, 38.4% and 37.0% achieved HBeAg seroconversion with HBV DNA <2000 IU/ml at EOF respectively. Conclusions: Patients with HBsAg <1500 IU/ml or HBV DNA <10(5) copies/ml at week 24 would benefit from continued PegIFN treatment. Extending the duration of PegIFN with or without adding adefovir did not show superiority over 48 weeks PegIFN monotherapy. Lay summary: Extending the duration of pegylated interferon (PegIFN) alfa-2a is not recommended in HBeAg positive patients as treatment extension beyond 48 weeks did not show convincing benefit. Patients who achieved HBsAg <1500 IU/ml or HBV DNA <105 copies/ml after 24-week PegIFN alpha-2a showed satisfactory outcome after the withdrawal of finite PegIFN alpha-2a treatment. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V.