Palonosetron is a new, potent and long-acting 5HT3-receptorsantagonist that had been approved by the FDA for use in postoperative nausea and vomiting (PONV) prophylaxis. The objective of this study was to investigate and compare the prophylactic effects of intravenously administered palonosetron, ondansetron and granisetron on prevention of postoperative nausea and vomiting after general anesthesia. This randomized double blind prospective clinical study was carried out in the Department of Anaesthesia, DMCH, Dhaka, Bangladesh from January 2014 to December 2015. A total of 102 patients who underwent laparoscopic cholecystectomy under general anesthesia, out of which patients who received Palonosetron were in Group A (n=34), patients who received Ondansetron were in group B (n=34) and patients who received Granisetron were in group C (n=34) and also the patients were selected randomly by lottery method. Statistical analyses of the results were obtained by using window based computer software devised with Statistical Packages for Social Sciences (SPSS-22). Nausea was found 3(8.8%) in group A, 8(23.5%) in group B and 6(17.6%) in group C. Vomiting was found 3(8.8%) in group A, 10(29.4%) in group B and 7(20.6%) in group C. Vomiting was significantly higher in group B compare with group A. For group B rescue anti-emetic injection motilon (metoclopramide hydrochloride) 5mg IV slowly was given. Palonosetron is effective prophylaxis against post operative nausea and vomiting.