To evaluate the cost-effectiveness of intracameral cefuroxime for postoperative endophthalmitis prophylaxis, and to determine the efficacy threshold necessary for alternative antibiotics to attain cost-effective equivalence with intracameral cefuroxime. Cost-effectiveness analysis. We study a hypothetical cohort of 100,000 patients undergoing cataract surgery as a part of the cost analysis. A cost-effectiveness model was constructed to analyze different antibiotic prophylactic regimens for postoperative endophthalmitis with intracameral cefuroxime as our base case. Efficacy was defined as the absolute reduction in rate of infection from background rate of infection, which was sourced from the literature. Antibiotic cost data were derived from the Red Book 2007 edition, and salary data were taken from the United States Bureau of Labor Statistics. Multivariate sensitivity analysis assessed the performance of antibiotic options under different scenarios. Cost per case of endophthalmitis prevented; theoretical maximal cost-effectiveness; efficacy threshold necessary to achieve cost-effective equivalence with intracameral cefuroxime; ratio indicating how many times more effective or less expensive alternative antibiotics would have to be to achieve cost-effective equivalence with intracameral cefuroxime. The cost-effectiveness ratio for intracameral cefuroxime is $1403 per case of postoperative endophthalmitis prevented. By comparison, the least expensive topical fluoroquinolone in our study, ciprofloxacin, would have to be >8 times more effective than intracameral cefuroxime to achieve cost-effective equivalence. The most expensive topical fluoroquinolones studied, gatifloxacin and moxifloxacin, would have to be > or =19 times more effective than intracameral cefuroxime to achieve cost-effective equivalence. A sensitivity analysis reveals that even in the worst case scenario for intracameral cefuroxime efficacy and with a 50% reduction in the cost of 4th-generation fluoroquinolones, gatifloxacin and moxifloxacin would have to be > or =9 times more effective than intracameral cefuroxime to achieve cost-effective equivalence. Administration of intracameral cefuroxime is relatively cost-effective in preventing endophthalmitis after cataract surgery. Owing to their high costs, many commonly used topical antibiotics are not cost-effective compared with intracameral cefuroxime, even under optimistic assumptions about their efficacy.