Importance: Anti-vascular endothelial growth factor (VEGF) agents are currently the mainstay of treatment for diabetic retinopathy (DR). Although effective, data on their systemic safety remains inconclusive, particularly in high-risk patient groups. Objective: To explore the systemic safety of intravitreal anti-VEGF agents among patients with diabetes. Design, Setting, and Participants: This was a retrospective, longitudinal population-based analysis of the Corporate Data Warehouse, a large-scale database of patients within the US Veteran Health Affairs. All patients 18 years and older with type 2 diabetes who were seen at any Veterans Affairs health care facility in the US between January 1, 2011, and December 31, 2012, were identified. Data were then extracted on incident systemic adverse events among this patient cohort from January 1, 2013, to December 31, 2017. All individuals with diabetes who did and did not receive anti-VEGF injections were included. Patients with a history of prior systemic adverse events and those who received an intravitreal injection between January 1, 2011, and December 31, 2012, were excluded. Data were analyzed from October 2019 to March 2023. Exposure: Anti-VEGF injection. Main Outcomes and Measures: Proportion of patients with any incident systemic adverse event, acute myocardial infarction, cardiovascular disease, or kidney disease at 1-, 3-, and 5-year follow-up. Results: A total of 1731782 patients (mean [SD] age, 63.8 [12.3] years; 1656589 [95.7%] male) with type 2 diabetes were included. DR was present in 476013 (27.5%), and 14022 (0.8%) received anti-VEGF injections. Of the total number of patients with type 2 diabetes, 321940 (18.6%) developed systemic adverse events between 2013 and 2017. The 5-year cumulative incidence of any systemic adverse event was 37.0% (5187/14022) in the injection group vs 18.4% (316753/1717760) in the noninjection group (P <.001). Anti-VEGF injections were independently associated with a higher likelihood of developing any systemic adverse event (odds ratio, 1.8; 95% CI, 1.7-1.9) when controlling for age, race, sex, ethnicity, tobacco use, severity of DR, Deyo-Charlson Comorbidity Index score, mean hemoglobin A1c, total number of injections, and statin use. Conclusion and Relevance: In this study, intravitreal anti-VEGF injections were independently associated with a higher likelihood of systemic adverse events among patients with diabetes.