Patients with atrial fibrillation (AF) are at increased cardiovascular risk. The CHA 2 DS 2 -VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, previous stroke, vascular disease, age 65 to 74 years, female gender) has been used to predict thromboembolic risk in patients with nonvalvular AF. We aimed to evaluate the association between the CHA 2 DS 2 -VASc score and the risk of acute myocardial infarction (AMI) and all-cause mortality in patients with AF treated with direct oral anticoagulants (DOACs). The study was based on the Clalit Health Services database. Included were 21,129 patients with nonvalvular AF treated with DOACs. Patients were stratified into four groups according to the CHA 2 DS 2 -VASc score. 1-9 The primary end point was the occurrence of AMI and all-cause mortality. During 21,129 patient-years, there were 1,253 incidents (5.9%) of AMI. A higher CHA 2 DS 2 -VASc score was associated with a significantly increased risk of AMI (7.8, 14.9, 23.9, and 35.3 cases per 1,000 person-years, for patients with CHA 2 DS 2 -VASc score of 1 to 2, 3 to 4, 5 to 6, and 7 to 9, respectively, p <0.001). Each 1-point increase in the CHA 2 DS 2 -VASc score was associated with a 27% increased risk of AMI. A higher CHA 2 DS 2 -VASc score was also associated with a significantly increased ll-cause mortality rate (21.7, 60.2, 103.9, 162.6 cases per 1,000 person-years, for patients with CHA 2 DS 2 -VASc score of 1 to 2, 3 to 4, 5 to 6, 7 to 9, respectively, p <0.001). All associations remained statistically significant after a multivariate analysis. In conclusion, among patients with nonvalvular AF treated with DOACs, the CHA 2 DS 2 -VASc score was associated with increased risk of AMI and all-cause mortality., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)