To determine if prophylactic etodolac would significantly reduce postendodontic pain, when compared with ibuprofen or placebo, 36 patients consented to single blind oral administration of either 400 mg of etodolac, 600 mg of ibuprofen, or a placebo, before conventional one-appointment root canal therapy. Patient-reported visual analog scale ratings of pain intensity were conducted upon initial clinical presentation, immediately postoperative, 4, 8, 12, 24, 48, and 72 h after initiation of root canal therapy. Results showed that prophylactic ibuprofen administration significantly reduced postendodontic pain at 4 and 8 h after initiation of root canal therapy, when compared with etodolac and a placebo. Patients with a periapical diagnosis of acute apical periodontitis or with a Phoenix abscess showed a significant increased need for additional medication after completion of root canal therapy, compared with all other periapical diagnoses.