Evidence of an effect by botulinum toxins is still lacking for most pain conditions. In the present randomized, placebo-controlled, crossover multicenter study, the efficacy of botulinum toxin type A (BTX-A) was investigated in patients with persistent myofascial temporomandibular disorders (TMD). Twenty-one patients with myofascial TMD without adequate pain relief after conventional treatment participated. A total of 50 U of BTX-A or isotonic saline (control) was randomly injected into 3 standardized sites of the painful masseter muscles. Follow-up was performed after 1 and 3 months, followed by a 1-month washout period, after which crossover occurred. Pain intensity at rest was the primary outcome measure, while physical and emotional function, global improvement, side effects, and clinical measures were additional outcome measures. There was no main difference between drugs (ANOVA; P=.163), but there was a significant time effect (P<.001), so BTX-A reduced mean (SD) percent change of pain intensity by 30 (33%) after 1 month and by 23 (30%) after 3 months compared to 11 (40%) and 4 (33%) for saline. The number of patients who received a 30% pain reduction was not significantly larger for BTX-A than after saline at any follow-up visit. The number needed to treat was 11 after 1 month and 7 after 3 months. There were no significant changes after treatment in any other outcome measures, with the exception of pain on palpation, which decreased 3 months after saline injection (P<.05). These results do not indicate a clinical relevant effect of BTX-A in patients with persistent myofascial TMD pain.