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PURPOSE: To determine the incidence of endophthalmitis following anti-vascular endothelial growth factor (VEGF) therapy at our institution and to identify potential risk factors for post-injection endophthalmitis DESIGN: Retrospective, single center cohort study PARTICIPANTS: All patients who received an intravitreal injection of an anti-VEGF medication between January 1, 2014 and March 31, 2017. METHODS: Current Procedural Terminology and International Classification of Diseases billing codes were used to identify instances of anti-VEGF administration and cases of endophthalmitis. Medical records and injection technique were carefully reviewed in each case. Multivariable logistic regression analysis was performed in a stepwise fashion to determine independent predictors of endophthalmitis based on injection protocol. MAIN OUTCOME MEASURES: Incidence of post-injection endophthalmitis and odds of endophthalmitis by injection technique with 95% confidence intervals (CI). RESULTS: A total of 154,198 anti-VEGF injections were performed during the time period of interest, resulting in 58 cases of endophthalmitis (0.038%, 1:2,659). After adjustment for confounders, both 2% lidocaine jelly (OR = 11.28, 95% CI: 3.39 – 37.46, p < 0.001) and 0.5% Tetravisc (OR = 3.95, 95% CI: 1.15 – 13.50, p = 0.03) use were independent risk factors for post-injection endophthalmitis. Lid speculum use, povidone iodine strength (5% vs. 10%), injection location (superior or inferior), conjunctival displacement, use of provider gloves, employment of a strict no-talking policy, use of subconjunctival lidocaine, and topical antibiotic use were not statistically significant predictors of post-injection endophthalmitis. There was no difference in endophthalmitis rate among the anti-VEGF agents (bevacizumab, ranbizumab 0.3 mg, ranibizumab 0.5 mg, and aflibercept). CONCLUSION: The incidence of endophthalmitis after anti-VEGF injections is low. Use of lidocaine jelly or Tetravisc may increase the risk of post-injection endophthalmitis.