Introduction The majority of totally blind individuals exhibit non-24-h circadian rhythms due to light signals not reaching the suprachiasmatic nucleus, resulting in Non-24-h Sleep–Wake Disorder (Non-24), a serious circadian rhythm disorder with no approved treatment. Tasimelteon is a novel circadian regulator in development for Non-24 with selective agonist activity for melatonin MT1 and MT2 receptors. Materials and methods Two phase III placebo-controlled studies in blind Non-24 patients assessed safety, efficacy and maintenance of effect of tasimelteon treatment (20mg/day). Circadian period was assessed from urinary 6-sulfatoxymelatonin (aMT6s) and cortisol. Clinical assessments included a Non-24 Clinical Response Scale (N24CRS), nighttime sleep, daytime naps and Clinical Global Impression of Change (CGIC). Results Entrainment Study (SET) (n=84): Tasimelteon entrained the circadian clock (aMT6s: 20.0% vs. 2.6%; cortisol: 17.5% vs. 2.6%), had more clinical responders on the N24CRS (23.7 vs. 0%), improved CGIC (2.6% vs. 3.4), increased sleep in the worst quartile of nights (LQ-nTST) (57% vs. 17min), and decreased nap duration in the worst quartile of days (UQ-dTSD) (46% vs. 18min), compared to placebo (p<0.05). Maintenance Study (RESET) (n=20): Tasimelteon-entrained patients were randomized to continued treatment or placebo. Tasimelteon maintained entrainment compared to placebo (aMT6s: 90% vs. 20%; cortisol: 80% vs. 20%). In treated patients, nighttime sleep (LQ-nTST) increased, and daytime sleep (UQ-dTSD) decreased, by 67 and 59min/day, respectively (p<0.05). During the run-in phase of the study, the rate of entrainment among tasimelteon treated patients ranged from 55% to 75% in subpopulation sensitivity analysis. Tasimelteon was safe and well-tolerated in both studies. Conclusion Tasimelteon entrained the circadian pacemaker in blind patients with Non-24, and caused significant clinical improvement in multiple measures of sleep, wake and global functioning. Discontinuation of tasimelteon abolished circadian entrainment, resulting in an hour less sleep each night and an hour more sleep each day. These studies demonstrate that tasimelteon is an effective circadian regulator, and that continued treatment is required to maintain entrainment and the resulting clinical benefits. Acknowledgements Support for the study was provided by Vanda Pharmaceuticals Inc. (ClinicalTrials.gov NCT01163032 and NCT01430754). Statistical and Analytical Support was provided by Dennis Fisher at ”P Less Than” company.