Purpose: To investigate the cost-effectiveness of prophylactic treatments against cystoid macular edema (CME) after cataract surgery in patients without diabetes. Setting: Seven ophthalmology clinics in the Netherlands and Belgium. Design: Prospective cost-effectiveness analysis using data from a European multicenter randomized clinical trial (ESCRS PREMED). Methods: Patients without diabetes planned for expected uneventful cataract surgery were randomized to topical bromfenac (Yellox, n = 242), topical dexamethasone (n = 242), or a combination treatment (n = 238). All relevant resources from a healthcare perspective were included in the cost analysis within a time horizon of 12 weeks postoperatively. The main effectiveness outcome was quality-adjusted life years (QALYs). The main cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER) based on the cost per QALY. Results: The study comprised 722 patients without diabetes. Total healthcare costs and QALYs were [Euro sign] 447 (US $562) and 0.174 in the bromfenac group, [Euro sign]421 (US $529) and 0.179 in the dexamethasone group, and [Euro sign]442 (US $565) and 0.182 in the combination group. Bromfenac was most costly and least effective (ie, strongly dominated). The ICER was [Euro sign]6544 (US $8221) per QALY for the combination group compared with the dexamethasone group. Assuming that the willingness to pay is [Euro sign] 20 000 (US $25 126) per QALY, the cost-effectiveness probability was 3%, 32%, and 65% in the bromfenac, dexamethasone, and combination groups, respectively. Conclusions: In patients without diabetes, combination treatment with topical bromfenac and dexamethasone was effective and cost-effective in preventing CME after cataract surgery compared with treatment with either drug alone. [ABSTRACT FROM AUTHOR]