To assess the effects of prophylactic lamivudine on reactivation and mortality following immunosuppressive therapy in hepatitis B surface antigen (HBsAg)-positive patients, we performed a meta-analysis. Systematic review and meta-analysis of randomized and nonrandomized prospective controlled trials and retrospective comparative case series were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS. The primary outcomes were virological reactivation, clinical reactivation and mortality. Secondary outcomes included hepatitis B virus (HBV)-related mortality, liver histology, discontinuation or disruption of immunosuppressive therapy, lamivudine-resistant HBV strains and adverse events. A total of 21 studies were included, two of which were randomized controlled trials. Clinical and virological reactivation were significantly reduced in the lamivudine group [odds ratio (OR) 0.09; 95% confidence interval (CI) 0.05-0.15 and OR 0.04; 95% CI 0.01-0.14 respectively]. All-cause mortality was significantly reduced in the lamivudine group (OR 0.36; 95% CI 0.23-0.56) which translates to only 11 patients who need to be treated to prevent one death. Lamivudine significantly reduced HBV-related mortality, and discontinuations or disruptions of the immunosuppressive treatment. No adverse effects of lamivudine were recorded, and resistance to lamivudine occurred in low rates. We demonstrated a clear benefit of lamivudine in terms of clinical and virological HBV reactivation, overall mortality, HBV-related mortality and interruptions or discontinuations in the immunosuppressive treatment. Lamivudine should be administered prophylactically to HBsAg-positive patients who are about to receive immunosuppressive therapy.