Abstract Disclosure: Y. Lin: None. S. Gupta: None. L. Shi: None. V.A. Fonseca: None. Background: As testosterone therapy (TTh) prescriptions are increasing rapidly, the cardiovascular (CV) safety of TTh remains controversial among observational studies and clinical trials. Our objective is to determine the CV safety of long-term TTh in adult men with testosterone deficiency (TD) in a real-world setting. Method: This is a multi-center retrospective study comparing testosterone-treated men with untreated men diagnosed with TD. A total of 2,683 men (18+ years) with confirmed TD diagnosis and continuous enrollment were extracted from the REACHnet electronic health records data from 1/1/2013-7/1/2022. The TD was confirmed by at least 2 TD diagnoses (ICD-9/10 codes 253, 257.1, 257.2, 257.8, 257.9, E23, E29.1, E29.8, E29.9) and with the serum testosterone level less than 350 ng/dl before the first recorded TD diagnosis. We further excluded patients with a malignancy history prior to the first TD diagnosis date. Propensity score matching (PSM) by 1:1 ratio based on age, race, Charles Comorbidity Index, and serum testosterone level was conducted among men with TD. The treated group of 928 patients who were compared to the untreated group of 928 patients who opted against taking TTh. The intent to treat analysis using Kaplan-Meier curves and Cox regressions was used to examine CV risk for major adverse cardiovascular events (MACE), defined as a composite outcome of myocardial infarction, stroke, and cardiovascular death. Results: The treatment and control cohorts with 928 patients each had a median follow-up of 3 years. After PSM, only body mass index, diastolic blood pressure, hyperlipidemia, hypertension, depression, and anxiety were statistically significant between treatment and control cohorts. The log-rank test for the cumulative MACE incidence was comparable (p-value>0.05). There were no statistically significant associations between TTh use and increased CV risk in the univariate Cox regression (Hazard Ratio (HR) [95% CI]: 1.01 [0.75-1.36]) and Cox regressions adjusted by the pre-existing MACE (HR [95% CI]: 0.98 [0.72-1.32]) and other baseline covariates (HR [95% CI]: 0.93 [0.68-1.26]). Conclusion: TTh use among adult males with TD was not found to be associated with increased CV risk in real-world clinical practice. Further studies are needed for TTH use in a high-risk population with cardiovascular risk factors. Presentation: 6/1/2024