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In an era of growing economic constraints on healthcare delivery, anesthesiologists are increasingly expected to understand cost analysis and evaluate clinical practices. Postoperative nausea and vomiting (PONV) are distressing for patients and may increase costs in an ambulatory surgical unit. The authors compared the cost-effectiveness of four prophylactic intravenous regimens for PONV:—4 mg ondansetron, 0.625 mg droperidol, 1.25 mg droperidol, and placebo.Adult surgical outpatients at high risk for PONV were studied. Study drugs were administered intravenously within 20 min of induction of nitrous oxide–isoflurane or enflurane anesthesia. A decision-tree analysis was used to group patients into 12 mutually exclusive subgroups based on treatment and outcome. Costs were calculated for the prevention and treatment of PONV. Cost-effectiveness analysis was performed for each group.Two thousand sixty-one patients were enrolled. Efficacy data for study drugs have been previously reported, and the database from that study was used for pharmacoeconomic analysis. The mean–median total cost per patient who received prophylactic treatment with 4 mg ondansetron, 0.625 mg droperidol, 1.25 mg droperidol, and placebo were $112 or $16.44, $109 or $0.63, $104 or $0.51, and $164 or $51.20, respectively (P = 0.001, active treatment groups vs. placebo). The use of a prophylactic antiemetic agent significantly increased patient satisfaction (P < 0.05). Personnel costs in managing PONV and unexpected hospital admission constitute major cost components in our analysis. Exclusion of nursing labor costs from the calculation did not alter the overall conclusions regarding the relative costs of antiemetic therapy.The use of prophylactic antiemetic therapy in high-risk ambulatory surgical patients was more effective in preventing PONV and achieved greater patient satisfaction at a lower cost compared with placebo. The use of 1.25 mg droperidol intravenously was associated with greater effectiveness, lower costs, and similar patient satisfaction compared with 0.625 mg droperidol intravenously and 4 mg ondansetron intravenously.