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Background: Operator-directed nurse-administered (ODNA) sedation with propofol (PRO) is the preferred sedation technique for catheter ablation of atrial fibrillation (AF) in many centers., Objective: The purpose of this study was to investigate whether dexmedetomidine (DEX), an α 2 -adrenergic receptor agonist, is superior to propofol., Methods: We randomized 160 consecutive patients undergoing first AF ablation to ODNA sedation by DEX (DEX group) vs PRO (PRO group), according to a standardized protocol. Patients were unaware of treatment allocation. The primary endpoint was a composite of inefficient sedation, termination/change of sedation protocol or procedure abortion, hypercapnia (transcutaneous CO 2 >55 mm Hg), hypoxemia (SpO 2 <90%) or intubation, prolonged hypotension (systolic blood pressure <80 mm Hg), and sustained bradycardia necessitating cardiac pacing. Secondary endpoints were the components of the primary endpoint and patient satisfaction with procedural sedation, as assessed by a standardized questionnaire given the day after ablation., Results: The primary endpoint occurred in 15 DEX group and 25 PRO group patients (19% vs 31%; P = .068). Hypercapnia was significantly more frequent in PRO group patients (29% vs 10%; P = .003). There was no significant difference for the other components of the primary endpoint, and no procedure was aborted. Patient satisfaction was significantly better among PRO group patients (visual analogue scale 0-100; median 100 in PRO group vs median 93 in DEX group; P <.001)., Conclusion: Efficacy of ODNA sedation with DEX was not different from that with PRO. Hypercapnia occurs less frequently with DEX, but patient satisfaction is better with PRO sedation. In selected patients, DEX may be used as an alternative to PRO for ODNA sedation during AF ablation., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)