OBJECTIVE: To identify and summarize randomized clinical trials (RCTs) that assessed the effectiveness of chemoprophylaxis to prevent leprosy in contacts of patients newly diagnosed with the disease. METHODS: All studies were extracted from Medline (PubMed 1966 to November 2008), the Cochrane Controlled Trials Register (number 3 2008), LILACS (1982 to November 2008), and Scirus (November 2008). Manual searches and searches of crossed references of assessed articles were also done. RCTs' risk of bias was assessed according to the methodology proposed by the Cochrane Collaboration. The main outcome measure was diagnosis of leprosy (secondary cases) in contacts of patients with the disease (primary cases). RESULTS: The search identified 320 references, from which 7 RCTs with a total of 66 311 participants were included and evaluated. The combined results from the RCTs favored chemoprophylaxis to placebo with 2-4 years of follow-up (6 RCTs, 66 107 participants, relative risk (RR) 0.59, 95% confidence interval (CI) 0.50-0.70, I² = 0 (I² describes percent total variation across studies caused by heterogeneity)). Single-dose rifampicin (21 711 participants, RR 0.43, 95% CI 0.28-0.67, number needed to treat 285), dapsone once or twice weekly for at least 2 years (3 RCTs, 43 137 participants, RR 0.60, 95% CI 0.48-0.76, I² = 0), and acedapsone every 10 weeks for 7 months (2 RCTs, 1 259 participants, RR 0.49, 95% CI 0.33-0.72, I² = 0) were significantly superior to placebo in preventing secondary cases of leprosy. CONCLUSION: Chemoprophylaxis is effective in lowering the incidence of leprosy in contacts of patients diagnosed with the disease.