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Background: Left atrial appendage occlusion (LAAO) is an accepted strategy for cardioembolic events prevention in patients with non-valvular atrial fibrillation (AF) unsuitable for anticoagulation. However, uncertainties persist regarding the benefit of LAAO in highly-comorbid patients. The aim of this study was to assess the impact of the CHA 2 DS 2 -VASc score beyond thromboembolic risk in predicting clinical outcomes in patients undergoing LAAO., Methods: 160 patients who underwent LAAO were included and categorized into two groups according to their stroke risk (89 with CHA 2 DS 2 -VASc >4 vs. 71 with lower risk). The coprimary endpoints were death and stroke at follow-up. Thromboembolic and bleeding events were compared to those predicted from CHA 2 DS 2 -VASc and HAS-BLED scores., Results: Over a median follow-up of 679 days, CHA 2 DS 2 -VASc >4 was associated with increased all-cause mortality compared with patients with lower thromboembolic risk (HR: 3.23; 95% CI: 1.28-8.19; p < 0.001). However, the rates of stroke after LAAO were not significantly different between risk groups. The observed annual rates of stroke and major bleeding were lower than predicted., Conclusions: Despite increased long-term mortality in patients with CHA 2 DS 2 -VASc >4, LAAO remains beneficial in reducing stroke and bleeding events in high-risk AF patients unsuitable for anticoagulation., (Copyright © 2020 Elsevier B.V. All rights reserved.)