BACKGROUND: There are little data on the efficacy of antiemetics for treating postoperative nausea and vomiting (PONV) in patients who received prior PONV prophylaxis. METHODS: 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. RESULTS: 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. CONCLUSIONS: Promethazine was significantly more effective than ondansetron for treating PONV after failed ondansetron prophylaxis. Promethazine 6.25 mg was as effective as higher doses.