Edoxaban is an oral factor Xa (FXa) inhibitor in clinical development for stroke prevention in patients with atrial fibrillation, an elderly population that frequently receives aspirin (ASA) and/or nonsteroidal anti-inflammatory drugs for concurrent illnesses. Three studies were conducted to evaluate the pharmacokinetic and pharmacodynamic interactions of edoxaban 60 mg coadministered with low-dose (100 mg) ASA, high-dose (325 mg) ASA, or naproxen (500 mg) in healthy subjects (n = 126). Template bleeding times (BT) were measured. Mean baseline (predose) BT for the 3 studies ranged from 4.72 to 6.13 minutes. Edoxaban administered alone increased BT by 21%-35% (4 hours post dose) from baseline. Concomitant administration of edoxaban with high-dose ASA, low-dose ASA, or naproxen increased BT approximately 2-fold showing an additive effect greater than either agent administered alone. Edoxaban pharmacokinetics were not affected by concomitant low-dose ASA or naproxen, but high-dose ASA increased systemic exposure of edoxaban by approximately 30%. The effects of edoxaban on prothrombin time, activated partial thromboplastin time, international normalized ratio, anti-FXa, and intrinsic FXa activity were not influenced by administration with ASA or naproxen. Inhibition of platelet aggregation by high-dose ASA, low-dose ASA, or naproxen was not affected by edoxaban. Concomitant administration of edoxaban and ASA or naproxen was well tolerated.