Abstract Introduction Insomnia and restless legs syndrome (RLS) are common sleep disorders that may impact obstructive sleep apnea (OSA) treatment. To our knowledge, no studies have investigated whether these comorbidities affect upper airway stimulation (UAS) therapy adherence and outcomes. This study aims to explore possible effects of insomnia and RLS in patients using UAS therapy. Methods All patients who underwent UAS system implantation for treatment of OSA at our facility were retrospectively studied. Pre- and post-implant histories and data, including diagnostic sleep testing, otolaryngology evaluation, activation results, and treatment evaluation, were analyzed. Patients with no insomnia or RLS were compared to patients with insomnia, RLS, or both. Apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), and adherence were compared pre- and post-treatment for each group. Results Sixty-four patients who have undergone UAS implantation at our center have completed post-treatment in-lab titration and evaluation of their UAS system. Insomnia was present in 47%, RLS in 28%, and both insomnia and RLS in 14%. In all groups, the overall AHI during in-lab titration was >50% lower than the pre-treatment AHI (16.1+/-14.3/h vs 32.5+/-13.1/h, p<0.001). While the trend in AHI reductions suggested a lower AHI in those without insomnia or RLS, the reduction did not reach statistical significance (no insomnia or RLS 15.7+/-12.9/h, insomnia 16.9+/-16.7/h, RLS 19.0+/-15.5/h, both insomnia and RLS 23.4+/-18.4/h). UAS therapy usage was reduced in patients with RLS (3.9+/-2.6 h/night, p=0.029) and in patients with both insomnia and RLS (3.9+/-1.3 h/night, p=0.046) compared to patients with neither comorbidity (5.9+/-1.9 h/night). Mean reduction in ESS was similar across groups, averaging from 11+/-5 pre-treatment to 7+/-5 post-treatment (p<0.001). Conclusion Insomnia and RLS are common in patients using UAS therapy for OSA. Pre- and post-treatment residual AHI and ESS significantly improved in all patient groups assessed. A decrease in UAS usage was present in patients with RLS and both RLS and insomnia. Our study suggests that identification and treatment of RLS and insomnia may play an important role for UAS therapy adherence and efficacy, thus, optimizing care. Support (if any):