BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.