Background and aims: Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as a clinical endpoint. The purpose of the present meta-analysis was to evaluate the effect of combined therapy with pegylated interferon alpha (PEG-IFN alpha) with or without lamivudine (LAM) or adefovir (ADV) on HBsAg seroclearance or seroconversion in subjects with chronic hepatitis B (CHB). Methods: Randomized controlled trials performed through May 30th 2015 in adults with CHB receiving PEG-IFN alpha and LAM or ADV combination therapy or monotherapy for 48-52 weeks were included. The Review Manager Software 5.2.0 was used for the meta-analysis. Results: No statistical differences in HBsAg seroclearance (9.9% vs. 7.1%, OR = 1.47, 95% CI: 0.75, 2.90; p = 0.26) or HBsAg seroconversion (4.2% vs. 3.7%, OR = 1.17, 95% CI: 0.57, 2.37; p = 0.67) rates were noticed between PEG-IFN alpha + LAM and PEG-IFN + placebo during post-treatment follow-up for 24-26-weeks in subjects with hepatitis Be antigen (HBeAg)positive CHB. No statistical differences in HBsAg clearance (10.5% vs. 6.4%, OR = 1.68, 95% CI: 0.75, 3.76; p = 0.21) were seen, but statistical differences in HBsAg seroconversion (6.3% vs. 0%, OR = 7.22, 95% CI: 1.23, 42.40; p = 0.03) were observed, between PEG-IFN alpha + ADV and PEG-IFN alpha for 48-52 weeks of treatment in subjects with HBeAg-positive CHB. A systematic evaluation showed no differences in HBsAg disappearance and seroconversion rates between PEG-IFN alpha + placebo and PEG-IFN alpha + LAM for 48-52 weeks in subjects with HBeAg-positive CHB. A systematic assessment found no differences in HBsAg disappearance and seroconversion rates between PEG-IFN alpha + placebo and PEG-IFN alpha + LAM during 24 weeks' to 3 years' follow-up after treatment in subjects with HBeAg-negative CHB. Conclusion: Combined therapy with PEG-IFN alpha and LAM or ADV was not superior to monotherapy with PEG-IFN alpha in terms of HBsAg seroclearance or seroconversion