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Abstract Context A recent US national survey of the health status of the male transgender population has raised awareness about the little-studied relationship between testosterone hormone therapy in transgender men and cardiovascular outcomes. Objective The aim of this systematic review was to assess the relationship between cross-sex hormone therapy in transgender men and lipid profiles and cardiovascular risk. Data Sources The PubMed, SciELO, SpringerLink, and EBSCOhost databases were searched up to March 2021 for studies assessing the association between cross-sex hormone therapy and the incidence of outcomes related to cardiovascular disease in transgender men over 18 years of age . Data Extraction Data extracted were sorted into clinical data (systolic, diastolic, and mean blood pressure), anthropometric data (body mass index, weight, waist circumference, fat mass, and lean mass), and biochemical data (triglycerides, total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], very low-density lipoprotein cholesterol [VLDL-C], and the HDL-C to LDL-C ratio). Data Analysis Study quality was appraised independently by two reviewers using the Cochrane tools for assessment of methodological quality or risk of bias in nonrandomized studies, and the Newcastle-Ottawa Scale was applied. Of 735 studies identified, 11 were included in the review. Most studies reported no change in cholesterol or triglyceride levels after hormone treatment. A reduction in HDL-C levels was observed in 7 of 11 studies, although this alone cannot be considered a cardiovascular risk factor. Likewise, clinical and anthropometric findings showed no changes predictive of cardiovascular risk. Conclusions Although these findings suggest that hormone therapy may lead to a decrease in HDL-C levels and an increase in LDL-C levels, they are insufficient to establish a relationship with cardiovascular disease. Furthermore, no significant effects on metabolic and anthropometric values were found. Further studies with higher quality and longer follow-up periods are needed to establish cardiovascular risk. Systematic Review Registration PROSPERO registration number CRD 42020212560.