To compare the efficacy and adverse effects of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with naproxen, a non-steroidal anti-inflammatory drug, and placebo in the treatment of painful temporomandibular joints (TMJs). In this randomized, double-blind, placebo-controlled trial, 68 subjects with painful TMJs secondary to disc-displacement with reduction, received celecoxib 100 mg twice a day; naproxen, 500 mg twice a day; or placebo for 6 weeks. Subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analogue scale, maximal comfortable mandibular opening, and quality of life (SF-36), at baseline (1 week after discontinuing previous analgesic therapy) and again after 6 weeks of drug treatment. Naproxen significantly reduced the symptoms of painful temporomandibular joint disc-displacement (TMJ DD) with reduction as determined by most efficacy measures. Significant improvement in pain intensity occurred within 3 weeks of treatment, and was sustained throughout the 6-week study. Clinically significant improvement in mandibular range of motion was observed for naproxen compared to celecoxib and placebo. Celecoxib showed slightly better pain reduction than placebo, but was not significantly effective for temporomandibular disorder pain. Celecoxib and naproxen were well tolerated, with similar number of reported adverse effects. Dual COX-1 and COX-2 inhibition with naproxen was demonstrated to be effective for the treatment of painful TMJs, as seen by significant improvement in clinical signs and symptoms of TMJ DD with reduction compared to celecoxib and placebo. Inhibition of both COX isozymes is needed to achieve effective analgesia for this type of musculoskeletal pain.