BACKGROUND: Azithromycin has been used for many years for the treatment of patients with various types of bacterial infections, as well as for the secondary prevention of coronary events. There is a growing concern, however, that azithromycin may be associated with an increased cardiovascular (CV) risk and may lead to CV-related death in high-risk patients. OBJECTIVE: This systematic review of randomized controlled trials was conducted to analyze and describe the CV risk and safety outcomes associated with azithromycin therapy. METHODS: A meta-analysis was conducted based on the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases from 1990 through September 2013. Specific medical search terms in the English language included “azithromycin,” “macrolide,” “antibiotic,” “cardiovascular diseases,” and “cardiovascular events” and were used to identify relevant randomized clinical trials that assessed the risk for CV events in patients receiving azithromycin therapy or placebo. The randomized clinical trials that were selected included patients who received azithromycin or placebo for the treatment of infection or for the secondary prevention of coronary events. Major health outcome measures included mortality, hospitalization, and coronary intervention. Meta-analyses were performed using a random effects model. RESULTS: A total of 12 randomized clinical trials included 15,588 patients. Patients were divided into 2 groups, either to azithromycin therapy or to placebo. Compared with patients who had not received azithromycin, patients who had received azithromycin had an overall risk ratio (RR) of death of 0.877 (95% confidence interval [CI], 0.752-1.024; P = .097). No heterogeneity was observed (I2 = 0%). Similarly, no differences were found in the pooled RRs for hospitalization or for clinical intervention for CV events (RR, 1.005; 95% CI, 0.922-1.094; P = .915; I2 = 0% and RR, 0.999; 95% CI, 0.896-1.125; P = .984; I2 = 0%, respectively). CONCLUSION: No increased risks for mortality or for CV events associated with azithromycin therapy compared with placebo were found among patients included in the 12 randomized clinical trials reviewed in this analysis.