The aim of this study was to compare the efficacy of intravenous granisetron and intravenous ondansetron for prevention of postoperative nausea and vomiting in patients undergoing total abdominal hysterectomy under general anesthesia. In this prospective double-blind randomized controlled clinical trial, 60 American Society of ASA Grade I and II patients aged between 18 and 60 years scheduled for elective total abdominal hysterectomy under general anesthesia were selected. The patients were divided in the following Groups of 30 patients each: Group 1 (Granisetron): 30 patients were given 1 mg of Granisetron was diluted in NS to make upto 10 ml; Group 2 (Ondansetron): 30 patients were given 4 mg of Ondansetron was diluted in NS to make upto 10 ml. Postoperative Nausea and Vomiting (PONV), hemodynamic and side effects were observed at scheduled intervals. The incidence of PONV was significantly lower in Group 1 (Granisetron) than in Group 2 (Ondansetron). Requirement of rescue antiemetic was significantly lower in Group 1 (Granisetron) 6.7% as compared to Group 2 (Ondansetron) 33.3%. . At all times the changes in the vital parameters like pulse rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure and SpO2 were within the normal physiological limits. There was no statistical significant difference between the groups. It was observed that there was no significant difference in adverse effects amongst the groups as well. We conclude that granisetron is more effective, potent and longer acting antiemetic as compared to ondansetron for reducing PONV in patients undergoing Total Abdominal Hysterectomy under general anesthesia.