In the last decade, PEG-IFNa-2a has been widely used in the treatment of chronic hepatitis B (CHB). The current standard duration is 48 weeks; however, several studies based on small sample sizes have indicated that treatment extended beyond 48 weeks improved clinical outcomes than standard 48 weeks of therapy. Therefore, we performed a meta-analysis to compare the efficacy and safety of extended duration versus standard duration treatment with PEG-IFNa-2a monotherapy for patients with CHB. Four studies comprising of 350 patients were included in our study. Our analysis showed that extended treatment resulted in a higher HBsAg clearance rate compared with the standard treatment at the end of treatment, 24 and 48 weeks post-treatment [odds ratio (OR)=2.45, 95% confidence intervals (CI) (1.17–5.11), P=0.02; OR=3.17, 95% CI (1.62–6.21), P<0.01; OR=5.02, 95% CI (1.63–15.45), P<0.01, respectively]. Higher HBeAg seroconversion rates were also obtained in the extended treatment group than the standard treatment group at the end of treatment and 48 weeks post-treatment [OR=2.09, 95% CI (1.10–3.98), P=0.02, and OR=2.67, 95% CI (1.39–5.13), P<0.01, respectively]. In addition, extended treatment was superior to standard treatment in HBV-DNA inhibition rate at 48 weeks post-treatment [OR=3.15, 95% CI (1.51–6.57), P<0.01]. Therefore, extended treatment with PEG-IFNa-2a beyond 48 weeks may be a promising strategy to achieve higher rates of sustained HBV-DNA inhibition, HBeAg seroconversion and HBsAg clearance off-therapy for patients with CHB.