© 2016 We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD). Methods Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors. Results A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2 mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P <.001) and heart failure (68% vs 59%; P <.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P = .95 for interaction), and major or NMCR bleeding (P = .76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P = .094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P <.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P <.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P = .009). Conclusions Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF.