OBJECTIVES: To test the safety and efficacy of onabotulinum toxin-A (BoNT-A) injections into the masseter and temporalis muscles in patients with symptomatic sleep bruxism. METHODS: Participants 18 to 85 years old with clinically diagnosed sleep bruxism confirmed by polysomnography were enrolled in this randomized, placebo-controlled, 1:1, parallel-design trial with open-label extension. Participants were injected with BoNT-A 200 units (60 into each masseter and 40 into each temporalis) or placebo and were evaluated at 4 to 8 weeks after the initial treatment visit. The primary efficacy endpoint was clinical global impression (CGI), and the secondary efficacy endpoint was a visual analog scale (VAS) of change in bruxism and in pain at 4 to 8 weeks after injection. Exploratory endpoints included modified Montreal Bruxism Questionnaire, Headache Impact Test-6, total Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Self-Rated Anxiety Scale, and polysomnography data, including EMG recordings of the masseter and temporalis muscle bruxing events. Adverse events were recorded. RESULTS: Thirty-one participants were recruited and 23 were randomized (19 female, age 47.4 ± 16.9 years). All 13 randomized to BoNT-A and 9 of 10 randomized to placebo completed the study. CGI (p < 0.05) and VAS of change (p < 0.05) favored the BoNT-A group. None of the exploratory endpoints changed significantly, but total sleep time and number/duration of bruxing episodes favored the BoNT-A group. Two participants randomized to BoNT-A reported a cosmetic change in their smile. No dysphagia or masticatory adverse events were reported. CONCLUSIONS: BoNT-A effectively and safely improved sleep bruxism in this placebo-controlled pilot trial. A large multicenter trial is needed to confirm these encouraging data. CLINICALTRIALSGOV IDENTIFIER: NTC00908050. CLASS OF EVIDENCE: This study provides Class II evidence that botulinum injections into the masseter and temporalis muscles improve subjective bruxism and painful symptoms associated with sleep bruxism.