The aim of this study was to systematically review the efficacy and safety of entecavir versus lamivudine for the treatment of chronic hepatitis B (CHB). A computerized search of The Cochrane Library (CENTRAL, Issue 5, 2011), MEDLINE (PubMed, 1978-June 2011), EMbase (1974-June 2011) and CNKI (1978-June 2011) databases was conducted. In addition, a manual search was made of the references of the included studies and relevant articles. The searches were restricted to studies published in Chinese or English from the time the database was created to June 2011. Studies were selected according to prespecified inclusion and exclusion criteria and then subjected for quality assessment and data extraction. Meta-analysis was performed using the statistical software (RevMan 5.1.1) provided by the Cochrane Collaboration. A total of 8 studies, all of which were randomized clinical trials (RCTs), involving 2178 patients with CHB were included. Subgroup analyses by treatment duration were conducted. The quality of the evidence was classified as moderate by the GRADED approach for all the included RCTs. Meta-analysis showed the following. Entecavir was associated with significantly improved liver histology, compared with lamivudine (RR 1.16, 95, CI [1.07, 1.26], P=0.0004). Patients were significantly more likely to experience HBV-DNA loss and have normalized ALT levels when treated with entecavir versus lamivudine for either 48 or 96 weeks (RR 1.65, 95, CI [1.37, 1.98], P<0.00001; RR 1.15, 95, CI [1.11, 1.20], P<0.00001, respectively). There were no statistically significant differences in the proportion of patients who achieved HBeAg loss or HBeAg seroconversion, or who developed adverse events between entecavir and lamivudine treatments (RR 1.03, 95, CI [0.83, 1.26], P=0.81; RR 0.92, 95, CI [0.75, 1.12], P=0.39; RR 1.09, 95, CI [0.92, 1.30], P=0.31, respectively). Current clinical evidence suggests that despite of short- or long-term use, entecavir appears to be more effective than lamivudine in reducing serum HBV-DNA load, improving liver histology, and normalizing ALT in patients with CHB. However, the probability for patients to experience HBeAg loss or HBeAg seroconversion, or the risk for adverse events seems to be similar between entecavir and lamivudine regimens.