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Introduction: The risk of thromboembolic events or death in patients treated with intravitreal anti-vascular endothelial growth factor (IVT anti-VEGF) is poorly described on a large scale and by molecule. This study aimed to assess the risk of myocardial infarction (MI), stroke, or death in new users of IVT aflibercept versus ranibizumab in real-world practice. Methods: A nationwide cohort study using the French National Health Insurance databases covering 99% of the French population was conducted in patients aged 18 years or older who initiated IVT therapy with ranibizumab or aflibercept between 2014 and 2018. Patients were followed for up to 6 years until December 31, 2019. The risks of MI, stroke, and death were compared in new aflibercept versus ranibizumab users using Kaplan–Meier and multivariate Cox proportional hazards models adjusted on sociodemographic characteristics and cardiovascular disease or risk factors. Subgroup analyses were performed according to history of ischemic heart disease or stroke, diabetes, indication for treatment, sex, age, and number of IVT anti-VEGF injections. Results: When compared to new users of ranibizumab (n = 174,794, mean age 76.0 ± 11.9 years, 59.2% female), new users of aflibercept (n = 76,242, mean age 76.6 ± 11.2 years, 59.2% female) did not have an increased risk of MI (n = 1523 incident MI, adjusted hazard ratio [aHR] 1.00; 95% CI 0.89–1.11), stroke (n = 2306 incident strokes, aHR 1.03; 95% CI 0.95–1.13), or death (n = 4135 deaths, aHR 0.98; 95% CI 0.92–1.05). However, a small but non-statistically significant increase in the risk of stroke was observed in new users of aflibercept versus ranibizumab among patients with diabetes (aHR 1.15; 95% CI 0.98–1.35), particularly those with diabetic macular edema (aHR 1.20; 95% CI 1.00–1.44). The remaining subgroup analyses did not change the results. Conclusion: Aflibercept and ranibizumab appear to have similar safety profiles with respect to the risk of MI, stroke, or death under real-world conditions of use. [ABSTRACT FROM AUTHOR]