Context: The efficacy and safety of testosterone replacement therapy (TRT) in hypogonadal men remain incompletely understood. Objective: To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to determine the effects of TRT on patient important outcomes and adverse events in hypogonadal men. Data Sources: We searched Ovid Medline, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus, from inception to 2March 2017. Study Selection: Randomized clinical trials assessing the efficacy and adverse events of TRT of at least 12 weeks compared with placebo in adult men with hypogonadism, defined by morning total testosterone #300 ng/dL and at least one symptom or sign of hypogonadism. Data Extraction: Reviewers working independently and in duplicate assessed the quality of RCTs and collected data on patient characteristics, interventions, and outcomes. Results: We found four RCTs (including 1779 patients) at low risk of bias. Compared with placebo, TRT was associated with a small but significant increase in sexual desire or libido [standardized mean difference (SMD): 0.17; 95% confidence interval (CI), 0.01, 0.34; n = 1383], erectile function (SMD: 0.16; 95% CI, 0.06, 0.27; n = 1344), and sexual satisfaction (SMD: 0.16; 95% CI, 0.01, 0.31; n = 676) but had no effect on energy or mood. TRT was associated with an increased risk of developing erythrocytosis (relative risk: 8.14; 95% CI, 1.87, 35.40; n = 1579) compared with placebo but had no significant effect on lower urinary tract symptoms. Conclusion: In hypogonadal men, TRT improves sexual desire, erectile function and sexual satisfaction; however, it increases the risk of erythrocytosis.