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There are little data on the efficacy of antiemetics for treating postoperative nausea and vomiting (PONV) in patients who received prior PONV prophylaxis.In this retrospective database analysis, we compared the efficacy of ondansetron with that of promethazine for treating PONV in adults receiving general anesthesia who failed ondansetron prophylaxis.Three thousand sixty-two patients received ondansetron and 752 received promethazine after failure of ondansetron prophylaxis. The complete response (no PONV and no further rescue) was 68% after administration of promethazine and 50% after ondansetron administration (P < 0.0001). There was no difference in complete response between 6.25 mg and higher doses of promethazine.Promethazine was significantly more effective than ondansetron for treating PONV after failed ondansetron prophylaxis. Promethazine 6.25 mg was as effective as higher doses.