BACKGROUND: Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems. OBJECTIVE: To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems. DESIGN: Randomised, double-blind, placebo-controlled, parallel study. SETTING: Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues. PARTICIPANTS: Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6-week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks. INTERVENTIONS: Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose. MAIN OUTCOME MEASURES: The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQL™), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated. RESULTS: A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant. CONCLUSIONS: On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05534585. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information.