<h3>Objective:</h3> To analyze the migraine-preventive efficacy of eptinezumab in patients with a dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH). <h3>Background:</h3> Eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, is approved for the preventive treatment of migraine and has demonstrated effectiveness in patients with CM. <h3>Design/Methods:</h3> PROMISE-2 (NCT02974153), a double-blind, placebo-controlled, phase 3 study, randomized adults with CM to intravenous eptinezumab 100mg, 300mg, or placebo at day 0 and week 12 (wk12), for 24 weeks total treatment. Endpoints included changes in monthly migraine days (MMDs), monthly days of acute headache medication (AHM) use, percentage of patients below International Classification of Headache Disorders (ICHD) thresholds for CM and MOH, and assessments of patient-reported outcomes (PROs): 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), and patient-identified most bothersome symptom (PI-MBS). <h3>Results:</h3> At baseline, 431/1072 (40.2%) patients with CM (eptinezumab 100mg [n=139]; 300mg [n=147]; placebo [n=145]) were diagnosed with MOH and averaged 16.7 MMDs. At wk12, mean MMDs decreased 8.4 (100mg) and 8.6 (300mg) from baseline, versus 5.4 placebo (P<0.0001 for both doses). At 24wks, 29.0% of eptinezumab-treated patients were below CM and MOH diagnostic thresholds versus 6.3% with placebo. Total monthly AHM use decreased 9.8 days [BR1] (100mg) and 8.4 days [BR2] (300mg) during wks 1–12 vs 5 days [BR3] with placebo. HIT-6 total scores improved 7.0 (100mg) and 7.8 (300mg) vs 4.1 points (placebo) at wk12. At wk12, 58.5% (100mg) and 67.4% (300mg) of patients indicated PGIC was “much” or “very much” improved vs 35.8% placebo. PI-MBS improvement with eptinezumab treatment over placebo was similar to PGIC. <h3>Conclusions:</h3> This post hoc analysis of patients with dual diagnoses of CM and MOH suggests that eptinezumab treatment resulted in greater reductions in MMDs and AHM use compared with placebo and is associated with sustained, clinically meaningful improvements in PROs. <b>Disclosure:</b> Dr. Marmura has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Marmura has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Supernus. Dr. Marmura has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Axsome. Dr. Marmura has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Marmura has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Upsher-Smith. Dr. Marmura has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Marmura has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Theranica. Dr. Marmura has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Amgen/Novartis. Dr. Marmura has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Lilly. Dr. Marmura has stock in Curelator. The institution of Dr. Marmura has received research support from Teva. The institution of Dr. Marmura has received research support from AbbVie. Dr. Marmura has received publishing royalties from a publication relating to health care. Dr. Marmura has received publishing royalties from a publication relating to health care. Dr. Marmura has received publishing royalties from a publication relating to health care. Dr. Diener has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Diener has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for TEVA. Dr. Diener has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Dr. Diener has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Dr. Diener has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Thieme. The institution of Dr. Diener has received research support from German Research Council. Dr. Cowan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Cowan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Cowan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie. Dr. Cowan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Cowan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. Dr. Cowan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for lundbeck. Dr. Cowan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for biohavenn. Dr. Cowan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbviie. Dr. Cowan has stock in Percept. Dr. Cowan has received intellectual property interests from a discovery or technology relating to health care. Dr. Cowan has received intellectual property interests from a discovery or technology relating to health care. Dr. Cowan has received publishing royalties from a publication relating to health care. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Axsome Therapeutics. Dr. Starling has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Starling has received personal compensation in the range of $0-$499 for serving as a Consultant for Med-IQ. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medscape. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurolief. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Everyday Health. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Allergan. Dr. Starling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for WebMD. Joe Hirman, PhD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck . Joe Hirman, PhD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Impel NeuroPharma. Thomas Brevig has received personal compensation for serving as an employee of H. Lundbeck A/S. Thomas Brevig has received personal compensation for serving as an employee of Gedeon Richter Plc.. Thomas Brevig has stock in H. Lundbeck A/S. Dr. Cady has received personal compensation for serving as an employee of Lundbeck. Dr. Cady has stock in Alder Biopharmaceutical.