PURPOSE:: To compare patients with acute endophthalmitis after intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors vs. steroids. METHODS:: Retrospective single-center, nonrandomized interventional study from 2013 to 2021.Patients underwent vitreous biopsy before initiating treatment and were divided into the following cohorts: (1) anti-VEGF managed medically (T&I–anti-VEGF), (2) anti-VEGF managed by immediate pars plana vitrectomy (PPV–anti-VEGF), and (3) steroid therapy and managed medically or by pars plana vitrectomy (steroid). RESULTS:: A total of 141 patients were analyzed. The steroid cohort demonstrated significantly worse presenting (median = 2.80 logarithm of the minimum angle of resolution [logMAR]; P ≤ 0.01) and final (median = 2.30 logMAR) best-corrected visual acuity compared with T&I–anti-VEGF (presenting: median = 2.00 logMAR; final: median = 0.40 logMAR) and pars plana vitrectomy–anti-VEGF cohorts (presenting: median = 2.30 logMAR; final: median = 0.48 logMAR). There was no significant (P = 0.33) difference in the final best-corrected visual acuity between T&I–anti-VEGF and pars plana vitrectomy–anti-VEGF cohorts. There were no significant (P ≥ 0.63) differences among cohorts in best-corrected visual acuity before acute endophthalmitis diagnosis (T&I–anti-VEGF: median = 0.40 logMAR; pars plana vitrectomy–anti-VEGF: median = 0.40 logMAR; steroid: median = 0.44 logMAR). Microbial cultures revealed similar profiles for all cohorts. CONCLUSION:: Acute endophthalmitis after intravitreal injection steroid therapy had worse outcomes compared with anti-VEGF therapy.