Background: There is a paucity of contemporary data assessing the implications of atrial fibrillation (AF) on major adverse cardiovascular events (MACE) in patients with or at high-risk for atherosclerotic disease managed in routine practice. Hypothesis: We sought to evaluate the 4-year incidence of MACE in patients with or at risk of atherosclerotic disease in the presence of AF. Methods: Using US MarketScan data, we identified AF patients ≥45 years old with billing codes indicating established coronary artery disease, cerebrovascular disease, or peripheral artery disease or the presence of ≥3 risk factors for atherosclerotic disease from January 1, 2013 to December 31, 2013 with a minimum of 4-years of available follow-up. We calculated the 4-year incidence of MACE (cardiovascular death or hospitalization with a primary billing code for myocardial infarction or ischemic stroke). Patients were further stratified by CHA 2DS 2-VASc score and oral anticoagulation (OAC) use at baseline. Results: We identified 625,951 patients with 4-years of follow-up, of which 77,752 (12.4%) had comorbid AF. The median (25%, 75% range) CHA 2DS 2-VASc score was 4 (3, 5) and 64% of patients received an OAC at baseline. The incidence of MACE increased as CHA 2DS 2-VASc scores increased (P-interaction<.0001 for all). AF patients receiving an OAC were less likely to experience MACE (8.9% vs 11.6%, P <.0001) including ischemic stroke (5.4% vs 6.7%, P <.0001). Conclusion: Comorbid AF carries a substantial risk of MACE in patients with or at risk of atherosclerotic disease. MACE risk increases with higher CHA 2DS 2-VASc scores and is more likely in patients without OAC.