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Background and Aims: Post-operative nausea and vomiting (PONV) is one of the most common complications in patients undergoing gynaecological surgeries under spinal anaesthesia (SA). Palonosetron has the unique property of controlling 'delayed chemotherapy-induced nausea and vomiting' when compared to older serotonin antagonists. This study compared the effectiveness of palonosetron with a combination of ramosetron and dexamethasone in preventing PONV. Methods: Sixty patients undergoing gynaecological surgeries under SA were randomly allocated into two groups of thirty each,to receive either a combination of 0.3 mg of ramosetron and 8 mg of dexamethasone intravenously (IV) (Group RD) or 0.075 mg of palonosetron IV (Group P). The incidence of PONV, number of complete responders (no nausea, vomiting or use of rescue anti-emetics) and severity of nausea were evaluated during intra- and post-operative period. Results: The incidence of complete responders during intraoperative period was 80.0% in Group RD and 76.7% in Group P (P = 0.074) whereas postoperatively at 0–2 h and 2–6 h, it was 73.3% and 83.3% in Group RD respectively as compared to 46.6% and 56.6% in Group P respectively (P = 0.016 and P= 0.024). The incidence of PONV during 24 h of post-operative period was 30.00% in Group RD as compared to 60.00% in Group P (P = 0.0195). Nausea severity score and use of rescue anti-emetics did not vary between the groups. Conclusion: Combination of ramosetron and dexamethasone is more effective than palonosetron alone in preventing PONV in patients undergoing gynaecological surgeries under SA.