Background: Postoperative nausea and vomiting (PONV) was termed "the big little problem" nearly a quarter century ago in an editorial .The past decade has witnessed the introduction of several significant innovations to combat PONV, but it still remains as big a problem as before because newer choices and confusions over standardization added side by side . The aim of this study is to compare the efficacy of palonosetron with that of granisetron and ondansetron in the treatment and prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. Methods: This randomized prospective comparative clinical study was carried out in the NIMS Medical College & Hospital, NIMS University, Jaipur, during the period of January 2013 to December 2013 amongst female patients of ASA grade I and II (ASA = American Society of anesthesiology) , scheduled for laparoscopic cholecystectomy under general anesthesia. A total number of 90 patients were selected and randomized into three groups of 30 patients each. Group-I was given inj. palonosetron (0.25 mg), Group-II was given inj. granisetron (1 mg) and Group-III was given inj. ondansetron (8 mg). One way analysis of variance (ANOVA) and Pearson"s Chi-square test were done as the tests of significance whenever applicable to compare the mean of different groups. Results: The incidence of nausea was 10% in Palonosetron-group while it was found to be 60% in Ondansetrongroup. The incidence of vomiting was 6.7% in group-I, 26.6% in group-II & 53.3% in group-III respectively. The difference was statistically significant between group I vs group II (p <0.05). 13.3% of patients in Palonosetron-group required rescue antiemetic, while in Ondansetron-group, it was 46.7%. Conclusions: To conclude, palonosetron greatly reduced the incidence of postoperative nausea and vomiting, and also the requirement of rescue antiemetic in postoperative period than granisetron and ondansetron. Patients were satisfied by using this drug. Palonosetron is more effective in comparison to granisetron and ondansetron in the prevention and treatment of postoperative nausea and vomiting after laparoscopic cholecystectomy.