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Background: Postoperative nausea and vomiting (PONV) is one of the complications which hamper the successful implementation of day care surgical procedure in spite of the availability of so many antiemetic drugs and regimens for its prevention. The aim was to compare the prophylactic effects of intravenously (IV) administered ondansetron and palonosetron on PONV prevention in patients undergoing laparoscopic gynecological surgery under general anesthesia. Methods: A prospective double-blind study comprised of 60 ASAI/II female patients between the age group of 25 and 40 years was carried out in the Departments of Anesthesiology and Obstetrics and Gynecology of our institute. Patients were randomly divided into two groups of 30 patients each in a double-blind manner. Group I received 8 mg of inj. ondansetron IV while group II received inj. palonosetron 0.075 mg IV 5 minutes before the induction of anesthesia. The need for rescue antiemetics, episodes of PONV and other side effects were observed for 6 hours in the postanesthesia care unit and thereafter complaints were received on phone after the discharge. At the end of study, results were compiled and statistical data was subjected to statistical analysis using Student two-tailed 't' and χ2 test and value of P<0.05 was considered significant. Results: The demographical profile of the patients was comparable. Twenty and 13.33% of the patients in group I had nausea and vomiting episodes postoperatively as compared to 6.67% and 3.33%, respectively, in group II which was statistically significant (P<0.05). Twenty percent of the patients in group I experienced significant post-op headache as compared to 6.67% in group II. The mean rescue dose of antiemetic was significantly higher (10.6 mg) in the group I as compared to group II (6.4 mg) (P=0.036). The rest of parameters were comparable and statistically nonsignificant. Conclusions: Palonosetron is a comparatively better drug to prevent the PONV in patients undergoing day care surgical procedures as compared to ondansetron as it has got a prolonged duration of action and favorable side-effects profile. [ABSTRACT FROM AUTHOR]