Introduction Children with Down syndrome (DS) are at very high risk for obstructive sleep apnea (OSA), with a prevalence of OSA of 50-79%. Current OSA treatments for children with DS have limited effectiveness, as positive airway pressure therapy is poorly tolerated and adenotonsillectomy is not curative in most children with DS. The combination of atomoxetine and oxybutynin (ato-oxy) is a promising OSA treatment in adults. Ato-oxy has been shown to improve upper airway hypotonia, a key feature of OSA in children with DS, thus it may be particularly effective for OSA in children with DS. Methods We performed a randomized, double-blind, crossover pilot trial examining the short-term efficacy of ato-oxy in 15 children aged 6 to 17 years with DS and OSA. Participants received 4 weeks of low dose (0.5 mg/kg atomoxetine and 5 mg oxybutynin) as well as 4 weeks of high dose (1.2 mg/kg atomoxetine and 5 mg oxybutynin) in random order. Participants underwent polysomnography as well as parent-reported health-related quality of life assessment using the OSA-18 at baseline and at the end of each dosing period. The primary study endpoint was reduction in obstructive apnea-hypopnea index (oAHI) from baseline. Paired t-tests were used to compare baseline to low and high dose ato-oxy. Results 15 participants qualified for randomization and 11 participants had complete data at all points. Baseline oAHI was 7.4 ± 3.7 (mean ± standard deviation), oAHI with low dose ato-oxy was 3.6 ± 3.3 (p=0.001 vs baseline) and oAHI with high dose ato-oxy was 3.9 ± 2.8 (p=0.003 vs baseline). There were no differences in sleep architecture or sleep efficiency between baseline and either dose of ato-oxy. OSA-18 total score was 51.5 ± 18.5 at baseline; improved to 44.6 ± 17.0 (p=0.09) at the end of 4-weeks of low dose ato-oxy; and improved to 45.5 ± 15.7 (p=0.37) at the end of high-dose ato-oxy therapy. The most common adverse effects were irritability and fatigue, and these were generally mild. Conclusion Ato-oxy is a promising treatment for OSA in children with DS. Support (if any) Funding provided by NIH (HL151254 and HD109777) as well as the Lumind-IDSC foundation.