OBJECTIVE(S): Hypoglossal nerve stimulation (HGNS) is safe and effective for patients with Down syndrome (DS) and severe persistent obstructive sleep apnea (OSA). Long-term outcomes for this patient population have not been evaluated. METHODS: A prospective single-group multicenter cohort study with 1-year follow-up was conducted between 2015 and 2021 among 42 adolescent patients with DS and severe persistent OSA. Here, we evaluate long-term outcomes in this patient cohort. Patients were evaluated with polysomnogram (PSG) at three timepoints: pre-implantation (timepoint 1), 1-year post-implantation (timepoint 2), and long-term follow-up (timepoint 3). RESULTS: Long-term follow-up data were available for 33 of 42 patients. Mean (SD) of timepoint 3 was 4.0 (1.9) years after implantation. Using a therapy response definition of a 50% decrease in Apnea Hypopnea INdez (AHI) from timepoint 1, the response rate was 69.7% (23/33) at timepoint 2 and 87.9% (29/33) at timepoint 3. From timepoint 1, there was a mean (SD) decrease in AHI of 12.7 (13.4) events/h at timepoint 2 and 15.7 (13.1) events/h at timepoint 3. The mean percentage change in AHI between timepoints 1 and 2 was -51.1% (95% CI: -32.8% to -69.3%) and between timepoints 1 and 3 was -59.6% (95% CI: -42.0% to -77.3%). CONCLUSION: Patients with DS and severe persistent OSA who undergo HGNS implantation may continue to experience improvement in PSG parameters at long-term follow-up. Future studies are needed to assess additional long-term outcomes in this patient population, including neurocognition and quality of life. LEVEL OF EVIDENCE: 3 Laryngoscope, 135:1218-1222, 2025.