Background: Post-operative nausea and vomiting (PONV) is a common cause of post-operative discomfort with incidence ranges from (50%-70%) after laparoscopic surgery. Objective: To compare the effectiveness of dexamethasone, ondansetron and alizapride as monotherapy administered intravenously in postoperative nausea and vomiting prophylaxis for patients with moderate to high risk for nausea and vomiting undergoing laparoscopic surgery under general anesthesia. Patients and Methods: The study population was 120 Egyptian patients from both sexes undergoing laparoscopic surgery under general anesthesia with endotracheal intubation at Al-Azhar University Hospitals (El Hussein Hospital and Bab Al-Sharya Hospital). Approval of the study was taken from the Ethics Committee of Al-Azhar University. Prior to initiation of the study, written informed consent of the patient was obtained after full explanation of elements contained in the research protocol. There were 4 study groups; Control group, ondansetron group, alizapride group and dexamethasone group. Results: Age, sex, smoking history, related history, duration of surgery, type of surgery, vital signs and postoperative pain severity did not have any significant value in our study. Comparing the 4 studied groups according to postoperative nausea and vomiting presence, time of incidence and number of episodes had a significant value. Conclusion: Intravenous 0.1 mg/kg of ondansetron is very safe and highly significant in control of postoperative nausea and vomiting (PONV), it is even more effective than using 50 mg of intravenous alizapride or 8 mg of intravenous dexamethasone as prophylaxis. Dexamethasone is slightly better than alizapride in control of postoperative nausea and vomiting.