BACKGROUND : Direct oral anticoagulants (DOACs) can reduce the frequency of cardioembolic stroke with non-valvular atrial fibrillation as well as or better compared to vitamin K antagonists (VKAs). However, whether taking DOACs prior to stroke can prevent acute major cerebral artery occlusion (MCAO) has not been fully elucidated. METHODS : We enrolled patients who underwent cardioembolic stroke or transient ischemic attack with non-valvular atrial fibrillation who were admitted to our hospital between April 2011 and February 2017. The patients were classified into four groups based on anticoagulant medications prior to stroke: no oral anticoagulant (No OAC), VKA below therapeutic range on admission, VKA within therapeutic range on admission, and the DOAC group. We compared clinical backgrounds, National Institutes of Health Stroke Scale (NIHSS) scores, and MCAO prevalence on admission. We identified those patients with MCAO and investigated factors related to MCAO. RESULTS : A total of 287 patients were enrolled in the study (200 No OAC; 49 VKA below therapeutic range; 21 VKA within therapeutic range; and 17 DOAC). Median and interquartile range of NIHSS scores for each group were 10.5 (4-22) for No OAC; 14 (4-22) for VKA below therapeutic range; 8 (6-17) for VKA within therapeutic range; and 3 (1-9) for DOAC (P = 0.041). The prevalence of MCAO in each group was 40% in No OAC; 35% in VKA below therapeutic range; 29% in VKA within therapeutic range; and 6% in DOAC (P = 0.040). In total, 103 patients were identified with MCAO on admission. Multivariate analysis revealed that taking DOACs prior to stroke was significantly associated with MCAO (OR, 0.09; 95% CI, 0.004-0.75; P = 0.023). CONCLUSIONS : DOACs were an independent factor negatively correlated with MCAO in acute cardioembolic stroke with non-valvular atrial fibrillation.