Children with Down syndrome (DS) are known to be at very high risk for obstructive sleep apnea (OSA), with a prevalence of up to 66%. OSA has been associated with neurocognitive impairment and impaired health- related quality of life (HR-QOL) in children with DS. Current treatments for OSA in children with DS include adenotonsillectomy and positive airway pressure (PAP) therapy. Unfortunately, treatment effectiveness is limited by a high risk of residual OSA after adenotonsillectomy and poor adherence to PAP therapy. OSA is prevalent among children with DS and is associated with neurocognitive impairment and impaired HR-QOL. Targeted therapies are needed to mitigate these negative effects of OSA in children with DS. Airway hypotonia during sleep has been identified as a cause of OSA in children with DS. Consistent with this, OSA treatment aimed at improving airway tone via hypoglossal nerve stimulation appears to be effective in adolescents with DS. However, use of hypoglossal nerve stimulation may be limited in children given that multiple revision surgeries would likely be necessary in younger children to adjust for growth over time. The combination of atomoxetine and oxybutynin (ato-oxy) was shown to improve airway tone during sleep and treat OSA in adults without DS. Given that both drugs are routinely used and well-tolerated in children, we hypothesize that ato- oxy will be an efficacious treatment for OSA in children with DS and will lead to improvement in neurocognition and HR-QOL. Specific aims of this project during the R61 phase include: Aim 1: To evaluate the short- term efficacy of ato-oxy treatment for OSA in children with DS. Aim 2: To evaluate the short-term efficacy of ato-oxy treatment on improving HR-QOL in children with DS and OSA. Specific aims of this project during the R33 phase include: Aim 3: To evaluate the long-term efficacy of ato-oxy treatment for OSA in children with DS. Aim 4: To evaluate the long-term efficacy of ato-oxy treatment on improving HR-QOL in children with DS and OSA. Aim 5: To evaluate the efficacy of ato-oxy treatment on improving neurocognition in children with DS and OSA. If successful, this project would identify a novel treatment for OSA in children with DS, as well as medication-based route to improve cognition in children with DS.