Postoperative pain management is a challenging problem in the clinical practice of endodontics. The aim of this study was to assess and compare the efficacy of local intraligamentary injection of dexamethasone and piroxicam on postoperative pain in mandibular molars with symptomatic irreversible pulpitis. Forty-two patients were included and randomly assigned to three equal groups (n=14). After administration of standard inferior alveolar nerve block, each participant received intraligamentary injection of 0.4 ml of either 8 mg/2 ml dexamethasone, 20 mg/ml piroxicam or 2% mepivacaine. Standard endodontic treatment was performed in a single visit. The pain was assessed by means of the Numerical Rating Scale preoperatively and postoperatively after 4, 6, 12, 24 and 48 hours. All demographic, baseline and outcome data were collected and statistically analyzed.There was no significant difference between the three groups regarding age, gender and preoperative pain. There was a significant reduction in pain in all groups, however, there was a statistically significant reduction in postoperative pain in piroxicam group compared to the mepivacaine group at all time intervals. There was a statistically significant reduction in postoperative pain in the dexamethasone group when compared to the mepivacaine group only at 4, 24 and 48 hours. However, there was no significant difference found at 6 and 12 hours. There was no significant difference between dexamethasone and piroxicam groups. It was concluded that preoperative intraligamentary injection of dexamethasone and piroxicam show a significant success in reducing postoperative pain compared to mepivacaine with no preference regarding using either of them.