ABSTRACT: A large percentage of children with Down Syndrome (DS) have obstructive sleep apnea (OSA) that is suboptimally treated by first-line surgical interventions. The persistence of OSA-related nightly intermittent hypoxemia and fragmented sleep may contribute to a cognitive impairment, as well as pulmonary vascular disease, myocardial dysfunction, reduced quality of life and daily functional impairment. While oxygen is sometimes used when other OSA therapies fail, its efficacy and safety have not been systematically studied. This R61/R33 is therefore designed to test the hypothesis that individuals with DS and moderate to severe OSA will have a safe and favorable response to low-flow oxygen treatment due to its effects on directly attenuating hypoxic episodes, with subsequent increased ventilatory stability and improvement in OSA. We further hypothesize that oxygen supplementation will lead to improvement in neurocognition, cardiac function, sleep, and quality of life. The R61 phase will actively engage families of patients with DS and our multi-stakeholder team to refine and pilot the protocol and recruitment strategies to ensure that we meet our recruitment/retention milestones in the R33 phase and we generate data most relevant to our patient population. In toto, we will screen approximately 328 children with DS and moderate to severe OSA, 5-17 yrs of age, who failed adenotonsillectomy, to identify oxygen responders, and then randomize 230 children to oxygen plus conservative therapy (OXT; administered using a patient-specific dose) or conservative therapy (CT) alone (weight management, sleep hygiene, nasal dilators) for 6 months. The primary outcome of the trial is working memory measured by co-primary endpoints that respectively assess caregiver-reported and objectively measured functions. Secondary outcomes include cardiac function and structure, right ventricular pressure, quality of life and sleep measures that will be collected under the supervision of experienced, central core laboratories. Six clinical sites experienced with pediatric clinical trials and established DS centers will participate in the trial. A Data Coordinating Center experienced with pediatric sleep trials with a strong history of working with these clinical sites will implement and monitor data quality control processes that addresses all stages of data handling. This study will fill a key knowledge gap in a potentially efficacious therapy for OSA, and provide evidence to support (or refute) the use of supplemental oxygen, as well as identify physiological markers to potentially identify patient subgroups most likely to experience benefit from this therapy.