<b><i>Background and Aims:</i></b> The aim of this study was to investigate the stroke mechanisms and associated conditions influencing the decision regarding stroke thromboprophylaxis in patients with atrial fibrillation (AF) plus ischemic stroke, according to the CHA₂DS₂-VASc score. <b><i>Methods:</i></b> We evaluated 938 consecutive patients with a diagnosis of AF plus transient ischemic attack/ischemic stroke. Based on the CHA₂DS₂-VASc scores, patients were stratified as score 0 or 1 (<i>n</i> = 151), score 2 (<i>n</i> = 146), score 3 (<i>n</i> = 213), score 4 (<i>n</i> = 185), or score ≥5 (<i>n</i> = 243). <b><i>Results:</i></b> Patients with a higher CHA₂DS₂-VASc score were more likely to have noncardioembolic stroke mechanism (<i>p</i> = 0.001). Large-artery atherosclerosis causing stenosis >50% was more frequently observed in the high CHA₂DS₂-VASc group (<i>p</i> < 0.001). Coronary artery disease and the use of antiplatelet agents were more prevalent in the higher group (<i>p</i> < 0.001). A high CHA₂DS₂-VASc score was associated with a higher frequency of cerebral microbleeds and a higher Fazekas grade for leukoaraiosis (<i>p</i> < 0.001). The HAS-BLED score was correlated with the CHA₂DS₂-VASc score (&#x03B3; = 0.650; <i>p</i> < 0.001). <b><i>Conclusions:</i></b> A higher CHA₂DS₂-VASc score is associated with noncardioembolic mechanisms of stroke and with a higher risk of bleeding. Strategies to treat macro/microangiopathy such as use of statin for plaque stabilization, as well as oral anticoagulants with a lower bleeding risk, are needed in these patients.