Background: Postoperative nausea and vomiting (PONV) are common after general anesthesia and patient controlled analgesia (PCA) using opioids. This study was designed to compare the effectiveness of ondansetron plus dexamethasone versus ondansetron alone in the prevention of PONV in a patient undergoing a PCA. Methods: We studied 166 ASA I, and II in-patients undergoing general anaesthesia for major gynecological surgery. After induction of anesthesia, Group 1 (n = 64) received intravenous (IV) dexamethasone 10 mg and Group 2 (n = 102) received IV saline 2 ml before the surgical incision. Each patient received IV meperidine 50 mg as a loading dose. Meperidine 5 mg/kg, ketorolac 3.6 mg/kg and ondansetron 8 mg diluted in 40 ml solutions were connected to PCA pump for postoperative pain control. Mean arterial blood pressure, heart rate, pain score and symptom-therapy score were checked at 1, 4, 8, 16, 24, and 36 hours after the PCA connection. Results: For Group 1 and Group 2, respectively, the overall incidence of PONV was 12.5% and 23.5%. The pain scores were lower in patients receiving a combination of ondansetron and dexamethasone than those on ondansetron alone at 4 hr (P < 0.05), 8 hr (P < 0.05) and 16 hr (P < 0.05). Conclusions: This study suggests that the combination of ondansetron and dexamethasone is not more effective than ondansetron alone in the prevention of postoperative nausea and vomiting in women having PCA following major gynecological surgery but is more effective for pain control.