Novel oral anticoagulants have recently been recommended for non-valvular atrial fibrillation, but have rarely been studied in the field of cardiac surgery. We prospectively investigated the safety of edoxaban, a novel oral anticoagulant, for use in cardiac surgery patients with postoperative atrial fibrillation (POAF), which is the most common complication of cardiac surgery and can lead to stroke. The subjects were adult cardiac surgery patients with POAF who received oral edoxaban for 2 months in an open-label pilot study. The primary endpoint was cerebrovascular/bleeding events up to 2 months, while the secondary endpoints were hemoglobin, prothrombin time, and activated partial thromboplastin time. There were no cerebrovascular or bleeding events during edoxaban treatment and the test drug was not discontinued by any patient. There was no macroscopic hematuria and hemoglobin did not decrease, being significantly higher than the baseline level after 2 months. The prothrombin time was significantly prolonged from 1 week to 2 months and the activated partial thromboplastin time was significantly prolonged from 1 day to 2 months. Echocardiography detected pericardial effusion in 1 patient, but hemoglobin did not decrease and the effusion improved with diuretic therapy. In conclusion, this pilot study demonstrated that edoxaban does not induce bleeding in patients with POAF after cardiac surgery, suggesting that it is safe to perform a large-scale efficacy study of edoxaban as anticoagulant therapy for POAF.