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Introduction Opioids are a consensus second-line treatment for moderate-to-severe restless legs syndrome (RLS). Due to its partial mu-opioid receptor agonist mechanism, buprenorphine (bup) has lower risk of respiratory depression, euphoria, and dependence than full-agonist opioids. We hypothesize that with long-term administration for severe RLS, bup is both effective and well-tolerated and can facilitate successful weaning off dopamine agonists (DA) for patients with augmentation. Methods We conducted a longitudinal examination of a retrospective cohort of patients prescribed bup over a 21-month period by a tertiary RLS specialist. Patient-reported outcomes were administered through patient-completed electronic health record-based questionnaires or by clinician interview: International RLS Study Group(IRLS-SG,primary outcome), Clinical Global Impressions of Improvement(CGI-I), Epworth Sleepiness Scale(ESS), Insomnia Severity Index(ISI), Patient Health Questionnaire(PHQ-9), and Patient-Reported Outcomes Measurement Information System-Sleep Disturbance domain(PROMIS-SD). A linear mixed model assuming compound symmetry correlation structure was used (least square means,95%CI) to test the change from baseline to 6-week, 3-month, 6-month, and 1-year intervals, and the final visit, irrespective of time from baseline, with adjustment of age, sex, other RLS meds at final visit, and administration of iron infusion. Results 55 patients (56.4% female, 64.9±12.1 years) started bup for RLS, and 42(76.3%) remained on bup at the final visit. IRLS-SG was 27.8(25.3,30.3) at baseline and was significantly reduced at every interval (p of trend < 0.001), including 11.4(7.4,15.4) at 1 year. Of the 39(70.9%) patients that were on a DA with augmentation at baseline, 32(82.1%) had discontinued DAs with 5(12.8%) on a reduced dose at the final visit. Of those remaining on bup at the final visit, 93.8% were CGI-I responders, There was a statistically significant longitudinal trend in 1-year improvement in ESS:9.9(8.0,11.8) to 6.9(4.5,9.4),p=0.003, ISI:18.0(15.9,20.1) to 15.0(11.6,18.3),p=0.048, PHQ-9:10.4(8.2,12.5) to 6.1(3.6,8.6),p< 0.001, and PROMIS-SD:63.0(60.2,65.7) to 53.8(49.8,57.8),p< 0.001. 13(23.6%) discontinued bup with nausea, cognitive complaints, and dizziness as the most common side effects. Conclusion In this largest cohort to date to examine buprenorphine in severe RLS, our findings show buprenorphine markedly reduced RLS symptoms, effectively enabled the elimination of dopamine agonists in patients with augmentation, improved sleep and other health quality measures, and was tolerated comparably to other RLS medications. Support (if any)