OBJECTIVE Chronic orofacial pain is often refractory to conventional pain therapies. We conducted an open-label study to determine whether adenosine 5'-triphosphate (ATP) could alleviate chronic intractable orofacial pain, and if so, which type of pain could respond to ATP. METHODS In 8 and 16 patients with non-neuropathic and neuropathic intractable orofacial pain, respectively, ATP was intravenously infused at a rate of 100 microgxkg(-1)xmin(-1) over 120 min. The magnitudes of spontaneous pain and brush-evoked allodynia were graded with a visual analog scale (VAS). When a VAS score for spontaneous pain was decreased by 50% or more by ATP, the patient was classified as a responder. RESULTS The patients could be clearly divided into 10 responders and 14 non-responders. Ten of the 16 patients (62.5%) with neuropathic pain, but none of the 8 patients with non-neuropathic pain, responded to ATP. In particular, all of 8 patients with neuropathic pain following pulpectomy, with or without subsequent tooth extraction, responded to ATP. In the 10 responders, VAS scores for spontaneous pain decreased slowly but progressively during the infusion period, and eventually, ATP reduced the VAS scores for spontaneous pain and allodynia by 82 +/- 15% and 74 +/- 9%, respectively. In these responders, the analgesic and anti-allodynic effects of ATP outlasted the infusion period for medians of 7 and 12 h, respectively. CONCLUSIONS Intravenous ATP did not relieve non-neuropathic orofacial pain. However, it exerted slowly expressed but long-lasting analgesic and anti-allodynic effects in patients with neuropathic orofacial pain, especially in those suffering from neuropathic pain following pulpectomy and/or tooth extraction.