The purpose of this double-blind, randomized study was to compare the effectiveness of ondansetron plus saline versus ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting. Of 180 women having general anesthesia for major gynecologic surgery, 89 received intravenous ondansetron, 4 mg, plus saline (Group 1) and 91 received intravenous ondansetron, 4 mg, plus dexamethasone 8 mg (Group 2) during their operation. A complete response, defined as no emesis and no need for rescue antiemetic during the 24-h postoperative period, occurred in 38% of patients in Group 1 and in 52% in Group 2 (P = 0.048). Emesis occurred in 34% of patients in Group 1 and in 15% in Group 2 (P = 0.003). Nausea scores were significantly lower for patients in Group 2 at 2 h (P = 0.023) and at 24 h (P = 0.001). In the ondansetron plus dexamethasone group, 9 out of 10 patients who received propofol for induction of anesthesia had no emesis. The only failure occurred in a patient who had a single emetic episode during the 24th postoperative hour. The combination of ondansetron and dexamethasone was more effective than ondansetron and saline in the prevention of postoperative nausea and vomiting for women having major gynecologic surgery.