Introduction: Post-operative nausea and vomiting is one of the most common and distressing side effect encountered by patients following anesthetic and surgical procedures. Aims: The aim of the present study is to compare the effectiveness of intravenously administered Granisetron with Metoclopramide in the prevention of post-operative nausea and vomiting in patients undergoing major gynecological surgery under general anesthesia. Materials and Methods: This study was carried out for a period a total number of 50 cases were taken into study 25 of them received Granisetron (40 μg/kg) and the other 25 patients received Metoclopramide (0.2 mg/kg) for preventing post-operative nausea and vomiting through a period of 24 hours. Results: There were no statistically significant differences between the groups with respect to patient's characteristics, type of surgery and duration of anesthesia. There was statistically significant increase in pulse rate and systolic blood pressure in metoclopramide group while the diastolic blood pressure remained relatively constant. Granisetron group did not show significant variation in either pulse rate or blood pressure. The incidence of post-operative nausea and vomiting in 24 hours period was 12% and 48% in granisetron and metoclopramide respectively. The incidence of nausea in first 24 hours of post-operative period was 12% and 48% in granisetron and metoclopramide groups respectively. The incidence of retching/vomiting in first 24 hours post-operative period was 32% in metoclopramide group and no such episodes occurred with granisetron. Conclusion: The administration of granisetron before induction of anesthesia is superior to metoclopramide in long-term prevention of post-operative nausea and vomiting following major gynecological surgery.