To compare the efficacy of intravenous ondansetron (4 mg, 2 mL) and granisetron (2 mg, 2 mL) for preventing postoperative nausea and vomiting (PONV) in patients during surgical procedures under general anesthesia. MATERIAL AND METHODS: A prospective, randomized, and double blind clinical study was carried out with 60 patients surgical procedures under general anesthesia. Patients were divided into two groups of 30 individuals each. Approximately 15 minutes before end of surgery, each patient received either 4 mg (2 mL) ondansetron or 2 mg (2 mL) granisetron intravenously in a double blind manner. Balanced anesthetic technique was used for all patients. Patients were assessed for episodes of nausea, retching, vomiting, and the need for rescue antiemetic at intervals of 0–6, 6–12, and 24 hours after surgery. Incidence of complete response and adverse effects were assessed at 24 hours postoperatively. Data was tabulated and subjected to statistical analysis using the chi–square test, unpaired t–test, A P–value less than 0.05 was considered statistically significant. RESULTS: There was no statistically significant difference between the two groups for incidence of PONV or the need for rescue antiemetic. Both study drugs were well tolerated with minimum adverse effects; the most common adverse effect was headache. The overall incidence of complete response in the granisetron group (86.7%) was significantly higher than the ondansetron group (60.0%). CONCLUSION: In conclusion, granisetron at an intravenous dose of 2 mg was found to be safe, well tolerated, and as effective as 4 mg intravenous ondansetron for antiemetic prophylaxis surgery patients receiving general anesthesia, and can be employed as routine antiemetic prophylaxis for PONV. It is a valuable alternative to ondansetron.