Background and Objective: Shivering is one of the most common problems after general anesthesia. Meperidine is the drug of choice to treat and prevent shivering, but it has dangerous side effects, particularly cardio respiratory depression. Ondansetron is another effective drug that has no dangerous side effects. The aim of this study was to compare Ondansetron and Meperidine with each other, and with placebo to prevent post anesthetic shivering. Materials and Methods: In this clinical trial, patients were randomly divided into three groups of 35. After injecting premedication, and immediately before induction of anesthesia, SaO2 Pulse oximetry was recorded. Patients in group O received Ondansetron 4mg IV, patients in group M received Meperidine 25mg IV, and patients in control (C) group received Saline 2ml IV. Similar method of general anesthesia was performed to all patients, and following awake extubation all were immediately transferred to recovery room. Within minutes 5 and 15 and after entrance to the recovery room, SaO2 was measured with Pulse oxymetry, and shivering was evaluated and recorded on the basis of a similar grading system. We used ANOVA, K-Square, and Tukey subtest to analyze the data. Results: Amount of shivering within minutes 5 and 15 after anesthesia was equal in groups O and M, and it was less than group C (P<0.05). In group O, the SaO2 did not drop during minutes 5 and 15 after anesthesia, while there was a slight reduction in groups M and C. Conclusion: It is concluded that Ondansetron 4mg IV, and Meperidine 25mg IV immediately before induction of anesthesia are equally effective to reduce post anesthetic shivering. Also, Ondansetron does not reduce SaO2. So, using Ondansetron instead of Meperidine is effective to prevent the post anesthetic shivering, especially in patients with cardio respiratory depression.