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Background and Aims: Patients undergoing ovarian cancer surgery after chemotherapy and requiring opioid-based patient-controlled analgesia (PCA) are at high-risk of postoperative nausea and vomiting (PONV). We aimed to assess the effect of palonosetron and dexamethasone combination for these patients for prevention of PONV. Methods: This study included 2 groups and 150 patients. At the time of wound closure, patients in group A received ondansetron 8 mg intravenous (IV) + dexamethasone 4 mg IV and group B received palonosetron 0.075 mg IV + dexamethasone 4 mg IV. Postoperatively for 48 hours, group A patients received ondansetron 4 mg 8 hourly IV, group B patients received normal saline 8 hourly IV in 2 cc syringe. The primary objective was the overall incidence of PONV. Independent t-test, Chi-square test, and Fisher's exact test were used and multivariate regression analysis was done. Results: Vomiting was significantly higher in group A (37.3%) as compared with group B (21.3%) at 0–48 hours (P = 0.031). Significantly more patients in Group A had nausea as compared with group B at 90–120 minutes (30.66% vs 18.66%, P = 0.043) and 6–24 hours (32.0% vs 22.66%, P = 0.029). PCA opioid usage in microgram was significantly higher in group A at 0–24 hours (690.53 ± 332.57 vs 576.85 ± 250.79, P = 0.024) and 0–48 hours (1126.10 ± 512.18 vs 952.13 ± 353.85, P = 0.030). Conclusion: Palonosetron with dexamethasone is more effective than ondasetron with dexamethasone for prevention of PONV in post-chemotherapy ovarian cancer surgeries receiving opioid-based patient controlled analgesia.