Abstract Introduction Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by excessive daytime sleepiness (EDS), with sleep inertia and prolonged nighttime sleep as key symptoms in many patients. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item self-reported questionnaire (0–50 score range; higher scores indicate greater severity). The IHSS assesses key symptoms (EDS, sleep inertia, prolonged sleep). An IHSS total score ≤22 is considered normal; the established minimum clinically important difference (MCID) is 4 points. This post hoc analysis evaluated response to lower-sodium oxybate (LXB; Xywav®) treatment on IHSS scores in a phase 3 clinical trial (NCT03533114). Methods Eligible participants with idiopathic hypersomnia began LXB treatment with an open-label treatment titration and optimization period (OLT; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). The IHSS was completed at baseline, during OLT (week [W]1, W4, W8, and end of OLT), and end of SDP. Response was defined as IHSS total score ≤22 or decrease in IHSS total score of ≥4 points after open-label LXB treatment. Results Participants were treatment naive (n=47) or taking alerting agents other than sodium oxybate at study entry (stable doses ≥2 months; n=62). At W1, W4, W8, end of OLT, and end of SDP, the percentage of participants achieving a response of total IHSS score ≤22 was 26.1%, 55.3%, 68.1%, 76.6%, and 80.9% (treatment-naive participants), respectively, and 24.2%, 53.2%, 60.7%, 71.0%, and 82.3% (participants taking alerting agents), respectively. At W1, W4, W8, end of OLT, and end of SDP, the percentage of participants achieving a response of total IHSS score decrease of ≥4 points was 45.7%, 80.9%, 83.0%, 97.9%, and 93.6% (treatment-naive participants), respectively, and 46.8%, 79.0%, 83.6%, 90.3%, and 98.4% (participants taking alerting agents), respectively. Treatment-emergent adverse events (≥10%) included nausea, headache, dizziness, anxiety, and vomiting. Conclusion Over 80% of participants achieved a clinically meaningful response based upon IHSS total score ≤22, and up to 98% demonstrated a decrease in total IHSS score of ≥4 points at end of SDP. The response rate defined by either parameter increased over the study period. The safety profile of LXB was consistent with that observed in narcolepsy. Support (If Any) Jazz Pharmaceuticals.