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Background: Percutaneous left atrial appendage occlusion (LAAO) is indicated in subjects with atrial fibrillation who cannot receive oral anticoagulants. This procedure requires transesophageal echocardiography guidance and is usually performed under general anesthesia. The Janus Mask is a new device designed to allow upper endoscopic procedures during noninvasive ventilation (NIV)., Aims: This study aims to assess the possibility of performing LAAO under sedation and NIV., Setting: Cardiac electrophysiology laboratory., Design: Case-control study., Materials and Methods: Data from 11 subjects undergoing LAAO under sedation and NIV with the Janus Mask were retrospectively collected. Procedure duration, outcomes, and physicians' satisfaction were compared with those of 11 subjects who underwent LAAO under general anesthesia in the same period., Statistical Analysis: Univariate analysis and analysis of variance for between-groups comparison., Results: The 11 subjects treated with sedation experienced a good outcome, with a high degree of satisfaction from the medical team. An increase in arterial partial pressure of carbon dioxide in the Janus group (45 [43-62] mmHg vs. 33 [30-35] mmHg in the general anesthesia group, P < 0.001) led to a transient pH decrease 45 min after the beginning of the procedure (7.30 [7.18-7.36] vs. 7.40 [7.39-7.46], P = 0.014). No differences in arterial partial pressure of oxygen, FiO 2 , and hemodynamic parameters were observed. The subjects' conditions at discharge from the recovery room were comparable. No difference in procedure duration was registered., Conclusions: LAAO procedure under sedation and NIV through the Janus Mask is safe and feasible. This strategy might represent a valuable alternative to manage such a compromised and fragile population.