Aims: To carry out a randomized clinical trial to compare the effect of palmitoylethanolamide (PEA) versus ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), for pain relief in temporomandibular joint (TMJ) osteoarthritis or arthralgia. PEA acts as an endogenous agent with an autacoid local inflammation antagonism and modulates mast cell behavior controlling both acute and chronic inflammation. Methods: A triple-blind randomized clinical trial was conducted on 24 patients (16 women and 8 men) aged 24 to 54 years and suffering from TMJ osteoarthritis or arthralgia. The patients were enrolled from a group of 120 consecutive patients referred to the University of Bologna's Department of Orthodontics. Patients were randomly divided into two groups: group A (12 subjects) -received PEA 300 mg in the morning and 600 mg in the evening for 7 days and then 300 mg twice a day for 7 more days. Group B (12 subjects) received ibuprofen 600 mg three times a day for 2 weeks. Every patient recorded the intensity of spontaneous pain on a visual analog scale twice a day. Maximum mouth opening was recorded by a blind operator during the first visit and again after the 14th day of drug treatment. A t test was used for data comparisons. Results: Pain decrease after 2 weeks of treatment was significantly higher in group A than in group B (P = .0001); maximum mouth opening improved more in group A than in group B (P = .022). Conclusion: These data suggest that PEA is effective in treating TMJ inflammatory pain. Schlagwörter: NSAIDs, palmitoylethanolamide, TMJ arthralgia, TMJ osteoarthritis, TMJ pain