To determine whether there is a difference in the risk of endophthalmitis after an intravitreal steroid injection compared with an anti-vascular endothelial growth factor (VEGF) agent injection. Retrospective cohort study. A total of 75,249 beneficiaries in a large national US medical claims database representing 406 380 intravitreal injections. Data were searched for all intravitreal injections (Current Procedural Terminology 67028) performed between 2003 and 2012. Cohorts were created on the basis of injections using anti-VEGF agents (bevacizumab, ranibizumab, aflibercept, and pegaptanib) and intraocular steroids (triamcinolone and dexamethasone). Endophthalmitis was defined as having a new endophthalmitis diagnosis (International Classification of Diseases 9th Revision 360.0x) and a "tap-and-inject" procedure (Current Procedural Terminology 67015, 67025), a vitrectomy (67036), or an intravitreal antibiotic injection on the same day, between 1 and 14 days post-injection. Exclusion occurred for any history of endophthalmitis, <6 months in the plan, or <1 month follow-up. The main outcome measure was the odds of endophthalmitis using logistic regression while controlling for injection-associated diagnosis, age, race, and gender. A total of 387,714 anti-VEGF injections and 18 666 steroid intravitreal injections were performed and followed by 73 (rate=0.019% or 1/5283 anti-VEGF injections) and 24 (rate=0.13% or 1/778 steroid injections) cases of endophthalmitis, respectively. After controlling for diagnosis, age, race, and gender, the odds ratio (OR) for endophthalmitis occurring was 6.92 (95% confidence interval, 3.54-13.52, P<0.001) times higher post-steroid injection compared with anti-VEGF injections. The rate of endophthalmitis post-intravitreal steroid injection in a national cohort was 0.13% (1/778 injections). This rate conferred a significantly increased OR of 6.92 for endophthalmitis compared with anti-VEGF agents.