To examine the feasibility, adherence to therapy, and efficacy of hypoglossal nerve stimulation (HGNS) in adults with Down syndrome (DS) with obstructive sleep apnea. Adults patients with DS who met criteria for hypoglossal nerve stimulation were prospectively enrolled. Objective adherence was extracted from a cloud-based compliance database. Pre-operative sleep studies were compared to follow-up testing performed no sooner than 3 months after device activation. Eleven adults with DS underwent implantation of HGNS between May 2021 and July 2024. Median age was 27 years old (interquartile range 26, 33), BMI 28.5kg/m2 (26.5, 32.4), 27% were female, and had severe OSA (apnea-hypopnea index (AHI) 40/hr, (28.4, 42.9)). All patients were successfully implanted on an outpatient basis with no post-operative complications or readmissions and activated on schedule at 1 month after surgery. Adherence data show nightly usage longer than 4 hours was 100% and 96% of nights and a median of 9.2 and 8.5 hours/night in the first 30 and 90 days, respectively. Seven patients have undergone follow up testing and the median entire night AHI was reduced by 76%. All patients experienced a >50% decrease in AHI and to less than 15/hr. Median time spent below 88% improved from 2.0% (0.3,5.0) to 0.2% (0,0.6), and oxygenation nadir improved from 79.0% (75.5,85) to 88.0% (86.5,91). In this small initial cohort, HGNS appears to be a safe, well-tolerated and efficacious treatment option for adults with DS with moderate-severe obstructive sleep apnea and positive airway pressure therapy intolerance.