Objective: To investigate the efficacy of sequential therapy with telbivudine in the treatment of HBeAg-positive chronic hepatitis B (CHB) patients with partial response after a standard course of interferon therapy. Methods: A retrospective cohort study was performed for 58 HBeAg-positive CHB patients with partial response at the end of interferon therapy (48-60 weeks) from January 2009 to December 2013. According to whether telbivudine was used sequentially or withdrawn at the end of the course of treatment, the patients were divided into telbivudine sequential therapy group and withdrawal group, and the two groups were compared with in terms of biochemical, virological, and serological response rates. The chi-square test, the t-test, and the non-parametric test were used based on data type. Results: A total of 58 patients were enrolled in this study, with 31 in the telbivudine sequential therapy group and 27 in the withdrawal group. At 12 and 24 weeks after interferon therapy ended, the telbivudine sequential therapy group had a significantly higher HBeAg clearance rate than the withdrawal group (22.6%/29.0% vs 0%/3.7%, P < 0.05). At week 48 of follow-up, the telbivudine sequential therapy group had a significantly higher combined response rate than the withdrawal group (22.6% vs 0%, P = 0.015). Among the 31 patients in the telbivudine sequential therapy group, 11 had an increase in creatine kinase during the administration of telbivudine. No patient in either group experienced serious adverse reactions during follow-up, such as muscular soreness, myositis, peripheral neuropathy, renal dysfunction, and liver function decompensation. Conclusion: In HBeAg-positive CHB patients with partial response to interferon therapy, sequential therapy with telbivudine can increase serological HBeAg clearance rate and combined response rate at week 48, and it is safe in HBeAg-positive CHB patients achieving partial response at the end of interferon therapy.