OBJECTIVE: To investigate whether addition of lamivudine to other antivirals was superior to single use of 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. References of included studies was also conducted. Randomized trials that compared lamivudine plus antiviral with single use of antiviral 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. Egger's regression was used to identify publication bias. Meta-regression and subgroup analysis were used to investigate heterogeneity. Type of comparison, duration, doses, and ethnicity were considered for heterogeneity. RESULTS: Fourteen trials were included, 78.6% of which were moderate to high quality. Ten trials studied addictive effect of lamivudine in interferon therapy, two in thymocin therapy, and two in other therapies. No publication bias was identified (coefficient=2.73, 95%CI=-0.96-6.42). Duration was a prognostic factor addressing heterogeneity in loss of HBeAg across trials. Short-term effect (<26 wks) of lamivudine plus antiviral was superior to antivral alone (OR=4.01, 95%CI: 1.83-15.8, P=0.000), but this effect disappeared in pronged duration (>26 wks, OR=0.61, 95%CI: 0.78-1.54). Ethnicity projected clinical difference in loss of HBV-DNA across trials. The combination of lamiuvdine with antiviral in Chinese patients produced significant loss of HBV-DNA (OR=3.58, 95%CI: 2.48-5.16). However, combination of lamivudine with interferon was not better than interferon alone. The combined therapy was superior to antiviral montherapy alone in normalization of ALT (OR=1.49, 95%CI=1.12-1.98). Loss of HBsAg was better in combined therapy (OR=1.72, 95%CI=1.05-2.81). Seroconversion were also better in combination therapy (OR=1.55, 95%CI=1.10-2.18), but this was not seen specifically in lamivudine plus interferon against interferon alone. CONCLUSIONS: Lamivudine is clinically useful to improve the antiviral effects in chronic hepatitis B patients.