Certain types of jaw-muscle pain may be managed with pharmacologic treatment. This study evaluated the effect of topical and systemic nonsteroidal anti-inflammatory drugs on acute postexercise jaw-muscle soreness. Ten men without temporomandibular disorders performed six 5-minute bouts of submaximal eccentric jaw exercise. The outcome variables were pressure pain thresholds and pain tolerance thresholds at the masseter muscles, and maximum voluntary occlusal force. Surface electromyography from the masseter muscles was used to assess the development of muscle fatigue during the exercise period. Three treatment modalities were tested in a placebo-controlled, double-blind approach: (A) placebo gel and placebo tablets; (B) nonsteroidal anti-inflammatory drug gel (2 g, 5% ibuprofen) and placebo tablets; and (C) placebo gel and nonsteroidal anti-inflammatory drug tablets (400 mg ibuprofen). The subjects used their medication 3 times a day for 3 days in the post-exercise period. In the exercise period, the mean power frequency of the electromyography signal, pressure pain threshold, pain tolerance threshold, and maximum voluntary occlusal force decreased significantly (analysis of variance, P .01). In the postexercise period, the effect of treatment on pressure pain thresholds was significant (F[2,9] = 4.41, P = .02). On day 3, treatment with topical nonsteroidal anti-inflammatory drugs was assoicated with significantly higher pressure pain thresholds as compared to treatment with systemic nonsteroidal anti-inflammatory drugs (P .05) and placebo (P .05). Treatment effects on pain tolerance thresholds and on maximum voluntary occlusal force were nonsignificant. The results demonstrated that repeated eccentric jaw exercise caused muscle fatigue and low levels of postexercise pain and soreness. Topical nonsteroidal anti-inflammatory drugs seem to have some advantages over systemic nonsteroidal anti-inflammatory drugs for management of exercise-induced jaw-muscle pain.