The purpose of this study was to evaluate the efficacy of lamivudine (LAM) versus telbivudine (LdT) in the treatment of chronic hepatitis B (CHB). Randomized controlled studies (RCTs) involving the use of LAM versus LdT in CHB patients were included in the study. Data were obtained from the Cochrane-controlled trials register, EMBASE and MEDLINE databases (1/1990 to 12/2011). Two reviewers performed quality assessment and extracted data independently. Eight RCTs were included in the main analysis. Eight eligible trials were included in the analysis. At the end of one-year treatment, LdT was better than LAM at the virological response (RR = 1.43, 95 % CI = 1.12-1.84, P = 0.005), while less than LAM at the viral breakthrough (RR = 0.34,95 % CI = 0.25-0.48, P < 0.00001), viral resistance (RR = 0.41,95 % CI = 0.28-0.58, P < 0.00001), but there was no statistically significant difference in the biochemical response (RR = 1.13,95 % CI = 0.99-1.29, P = 0.06), HBeAg seroconversion (RR = 1.13,95 % CI = 0.92-1.39, P = 0.25), therapeutic response (RR = 1.22,95 % CI = 1.00-1.50, P = 0.05) and adverse events (RR = 1.07,95 % CI = 1.00-1.14, P = 0.05). The creatine kinase (CK) elevation occurred more frequently in the LdT group than in LAM group (RR = 2.43,95 % CI = 1.57-3.75, P < 0.0001). When treatment prolonged to 2 years, LdT was better than LAM at the HBeAg seroconversion (RR = 1.29,95 % CI = 1.12-1.50, P = 0.0007) and therapeutic response (RR = 1.34,95 % CI = 1.21-1.49, P < 0.00001). LdT was more effective in inhibiting HBV replication and promoting HBeAg seroconversion than LAM for CHB patients, whereby adverse effects such as CK elevation must be paid attention to.