Abstract Introduction THN3 was the first reported parallel-arm, randomized controlled trial (RCT) of hypoglossal nerve stimulation (HGNS), wherein targeted HGNS (THN) was shown to be safe and efficacious at ameliorating sleep disordered breathing in patients with moderate to severe OSA and BMI≤35kg/m2 without screening with drug-induced sleep endoscopy. Unique among reported HGNS trials, separate cohorts of patients receiving early and late THN were followed longitudinally. Methods Measurements of apnea-hypopnea index (AHI) were available Pre-enrollment, Baseline (2 nights), Month 4 and Month 12/15. Except for Pre-enrollment, AHI values were calculated by an independent core laboratory from polysomnographic recordings. All subjects with complete data were included for analysis. AHI trajectories were constructed for early and late THN activation (Treatment[T], N=83, Month 1 and Control[C], N=45, Month 4, respectively) by computing median values. Confidence intervals were calculated by bootstrapping each median (N=30,000). Patient-reported outcome measures (PROMs) were treated similarly. Results AHI (Median (95% CI)) trajectories demonstrated a consistent pattern of pre-implant alignment (Pre-enrollment T:39.1 (36.0-45.0), C:38.0 (32.0-41.0); Baseline 1 T:36.1 (33.0-39.9), C:31.3 (27.2-38.6); Baseline 2 T:37.0 (34.3-41.0), C:35.2 (32.3-38.2)), divergence at the conclusion of the randomization period (Month 4 T:15.6 (11.9-25.3), C:30.6 (23.7-38.6)) and reconvergence following 11 months of treatment (Month 12/15 T:20.7 (16.0-26.4), C:18.1 (16.3-23.3)). Non-standardized Pre-enrollment AHI was slightly higher than Baseline values. Trajectories were similar for oxygen desaturation index (Baseline 1 T:35.3 (31.9-38.0),C:34.3 (27.5-40.3); Baseline 2 T:37.1 (33.4-39.3),C:36.8 (33.9-38.3); Month 4 T:19.5 (16.2-28.5), C:33.8 (25.4-41.1); Month 12/15 T:19.5 (16.0-25.6), C:19.7 (16.3-26.0)), the Epworth Sleepiness Scale (Baseline T:11.0 (10.0-13.0),C:11.5 (8.5-14.0); Month 4 T:6.0 (5.0-7.0), C:11.5 (8.0-12.5); Month 12/15 T:6.0 (4.0-7.0), C:5.5 (4.5-6.0)), the Functional Outcomes of Sleep Questionnaire (Baseline T:15.3 (14.0-16.5),C:14.7 (13.3-16.6); Month 4 T:18.3 (17.7-18.8), C:16.7 (14.9-17.7); Month 12/15 T:18.8 (18.3-19.3), C:18.5 (17.5-19.5)) and the Snore Outcomes Survey (Baseline T:26.6 (21.9-31.3),C:21.9 (18.8-31.3); Month 4 T:60.9 (56.3-67.9), C:29.7 (23.4-42.9); Month 12/15 T:62.5 (59.4-68.8), C:68.8 (62.5-71.9)). Conclusion Group trajectories of sleep-disordered breathing and PROMs further demonstrate the robust effects of THN in patients with moderate to severe OSA and the value of parallel-arm RCTs. Similar results may be expected in the ongoing OSPREY confirmatory trial of THN. Support (If Any) LivaNova