Context: The risks of testosterone therapy in men remain poorly understood. Objective: The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men. Data Sources:Wesearched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies. Study Selection: Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility. Data Extraction: Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data. Data Synthesis: The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weightedmeandifference (WMD), 0.80 g/dl;95%confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. Conclusions: The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment inmen in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up. Copyright © 2010 by The Endocrine Society.