To assess the effectiveness of intracameral phenylephrine/ketorolac during cataract surgery compared with postoperative topical steroids in reducing incidence of postoperative clinical cystoid macular edema (CME) confirmed via optical coherence tomography (OCT), breakthrough iritis, pain, and photophobia.Ambulatory surgical center/clinical practice.Retrospective 2-cohort study.This study of cataract surgery patients compared the incidence of postoperative CME, breakthrough iritis, pain, and photophobia between patients receiving either intracameral phenylephrine/ketorolac 1.0%/0.3% during surgery or topical loteprednol 0.5% 2 days preoperatively, tapered postoperatively. Patients with prior CME or at high risk for postoperative CME, combined cataract/glaucoma surgery, and medication protocols different from those studied here were excluded. All eyes received bromfenac 2 days preoperatively and 10 weeks postoperatively.The study enrolled 2218 eyes (n=1402). The phenylephrine/ketorolac treatment group included 1334 eyes (n=830) and the topical loteprednol control group included 884 eyes (n=572). The groups were comparable in age, race, gender, and perioperative characteristics. Clinical CME incidence was significantly lower in the phenylephrine/ketorolac group (0.52% vs 1.47%, P=0.021). The phenylephrine/ketorolac group also had significantly lower breakthrough iritis (1.72% vs 4.86%, P<0.001) and pain (1.27% vs 4.19%, P<0.001) than the topical loteprednol group. The incidence of photophobia trended lower for the phenylephrine/ketorolac group relative to the topical loteprednol group (0.90% vs 1.13%, respectively , P=0.590) but was not statistically significant.Intracameral phenylephrine/ketorolac and topical NSAIDs without postoperative topical steroids significantly reduced postoperative clinical CME, breakthrough iritis, and pain after cataract surgery when compared with conventional perioperative topical steroids and NSAIDs.