Postoperative pain following root canal therapy in of concern for the patient and dentist. Despite the fact that the pain relief afforded by endodontic treatment is effective، it is rarely immediate and complete. The purpose of this study was to compare the efficacy of amitriptyline with ibuprofen in controlling of post-endodontic pain. This randomized double-blind placebo controlled clinical trial included 75 patients with symptomatic vital molar which presented with moderate to severe endodontic pain. Patients were randomly allocated in one of 3 groups to receive uniform capsules containing placebo، ibuprofen 600mg or amitriptyline 50mg as single dose 90 min before root canal treatment. Pain intensity was recorded in Visual Analogue Scale (VAS) chart in defined times before، during and after treatment by patients. Data was statistically analyzed by Repeated Measures ANOVA and Tukey test. Statistically significant differences in mean pain score was seen between ibuprofen and amitriptyline groups with placebo group during، and 12، 18، 24، 36، 48 hours after treatment; but the difference was not significant at 6، 60، 72 hours after treatment. The difference between amitriptyline group and ibuprofen group was not statistically significant at any time. The results showed that amitriptyline administration is as effective as ibuprofen in management of post-endodontic pain in patients presented with moderate to severe pain.