The purpose of this prospective research was to evaluate the post-endodontic pain-reducing effect of piroxicam (feldene), a non-selective non-steroidal anti-inflammatory drug. Pain following endodontic treatment is often linked to the inflammatory process as well as additional central mechanisms. The effects of intraligamentary injection of piroxicam have not previously been studied. Sixty-five patients with irreversible pulpitis were randomly divided into two groups. The active group received intraligamentary injections totalling 0.4 mL of piroxicam, while the placebo group received the same amount of lidocaine. One-appointment endodontic therapy was performed by a single endodontist. Visual Analogue Scale was used to record pain before treatment and 4, 8, 12, 24 and 48 h postoperatively. The decrease in the intensity of post-treatment pain between the two groups was very significant. Intraligamentary injection of piroxicam can be considered an effective method for reducing post-endodontic pain. © 2010 The Authors. Australian Endodontic Journal © 2010 Australian Society of Endodontology.