OBJECTIVES: Exogenous testosterone products are widely used for symptoms of hypogonadism. Their cardiovascular safety remains uncertain. We evaluated whether exogenous testosterone therapy is associated with serious cardiovascular events. METHODS: We searched Pubmed, MEDLINE, EMBASE, Cochrane Collaboration Clinical Trials, clinicaltrials.gov, and the US Food and Drug Administration website, through August 28, 2015. Randomized controlled trials (RCTs) and observational studies which enrolled men > 18 years receiving testosterone for > 3 days were included. Two reviewers independently conducted all stages of review, with adjudication by a third reviewer when necessary. The primary outcomes were death due to all causes, myocardial infarction, and stroke. Secondary outcomes included heart failure, arrhythmia, and cardiac procedures. The risk of bias of RCTs and observational studies was evaluated using the Cochrane Collaboration tool and the Newcastle and Ottawa scale, respectively. The Peto odds ratio was used for meta-analysis. PROSPERO (#CRD42015019259). RESULTS: A total of 39 RCTs and 10 observational studies were included. Meta-analysis was conducted on 30 RCTs. Compared to placebo, exogenous testosterone treatment did not show any statistically significant increase in risk of myocardial infarction (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.39-1.93, 16 RCTs), stroke (OR 2.17, CI 0.63-7.54, 9 RCTs) or mortality (OR 0.88, CI 0.55-1.41, 20 RCTs). Sensitivity analysis showed similar results. The design and methodology of the studies were poorly reported. Observational studies showed conflicting results with marked clinical and methodological heterogeneity. CONCLUSIONS: We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke or mortality, although the evidence was imprecise. Our results may differ from previous reviews because of choice of outcomes and analytic approaches used. The low quality of the evidence precludes definitive conclusion.