OBJECTIVE: To investigate effectiveness of lamivudine monotherapy compared to other antivirals for patients with chronic hepatitis B. METHODS: Systematic review and meta-analysis of randomized trials were conducted. Medline, Cochrane Trial Register, Current Contents, SCI-E and CBMdisc were searched. Complementary screening of references of included studies was also conducted. Randomized trials that compared lamivudine monotherapy with single use of other antivirals for patients with chronic hepatitis B were eligible. Studies that included patients with co-infection of HCV and HIV, and with decompensate liver diseases were excluded. Outcomes measures were loss of HBeAg, seroconversion, loss of HBV-DNA, and normalization of ALT. Egger's regression and funnel plot were used to identify publication bias. Meta-regression, subgroup analysis and sensitivity analysis were used to investigate heterogeneity. Type of comparison, duration, doses, and ethnicity were considered for heterogeneity. RESULTS: A total of eleven included trials formed thirteen comparisons, without publication bias identified (coefficient=-1.52, 95%CI: -3.85-0.81). Of these, seven compared with interferon-alpha, five with nucleic analogues, and one with thymocin-alpha. Seven of eleven trials (63.6%) were moderate in quality, and three trials (27.3%) were high. Lamivudine was inferior to other antivirals in loss of HBeAg (OR=0.45, 95%CI: 0.30-0.67), without heterogeneity identified (chi-square=5.47, df=6, p=0.485). Although heterogeneous across trials in loss of HBV-DNA (chi-square=47.33, df=11, p=0.000), no specific factors were identified. It showed that lamivudine was comparable to other antivirals (OR=1.39, 95%CI=0.67-2.88). The comparison of lamivudine with interferon also identified no significant difference. Ethnic difference was the prognostic factor for addressing heterogeneity in normalization of ALT (coefficient=2.56, 95%CI=0.62-4.51, P=0.015). Lamivudine could produce more significant normalization of ALT than other antivirals in Chinese. Lamivudine was comparable to other antivirals in seroconversion. CONCLUSIONS: There was advantage of lamivudine in normalization of ALT. However, it was clinically inferior to other antivirals in decreasing HBeAg.