Context: In the modern era of surgical field laparoscopic surgeries are more frequently performed than open surgeries. Postoperative nausea and vomiting is a common complaint encountered in the patients who have undergone laparoscopic surgeries because of pneumoperitoneum created by CO2. A number of anti-emetics are given as prophylactic agents to prevent postoperative nausea and vomiting. Among them 5-hydroxytrypatmine type 3 receptor antagonists are highly effective in prevention and treatment of PONV. With this background we conducted a study for evaluating the effectiveness of two 5-HT3 receptor antagonists in prevention of PONV in patients undergoing laparoscopic surgeries under general anesthesia. Aim: To compare the efficacy and safety profile of two 5 HT3 antagonists namely palonosetron and ondansetron in the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic surgeries. Settings & Design: This was a prospective, randomized, single-blind comparative study. Sixty patients of age group between 18-60 years of Ameri can Society of Anaesthesiologists physical status class I and II undergoing laparoscopic surgeries were enrolled. They were randomly allocated into two groups namely Group A and B with 30 patients in each group. Group A received 0.075mg of injection palonosetron and Group B received 4mg of injection ondansetron intravenously 30 minutes before induction of anaesthesia. Statistical Analysis used: Statistical work up was performed using the SPSS version 16. Student’s t –test was used for quantitative data and Chi- square test was used for qualitative data. P value of less than 0.05 was found to be statistically significant. Results: The incidence of PONV in group A (palonosetron) was found to be 13% which is lesser than group B (ondansetron) where the incidence was 23%. The need for rescue antiemetic was also comparatively lesser in group A than group B. (23% vs 51%). The number of complete responders were 26 (86%) and 23 (76%) for palonosetron and ondansetron respectively. Conclusion: Palonosetron is effective antiemetic for preventing PONV during the late postoperative period while compared to ondansetron.