Background and Purpose The aim of this study was to investigate for a possible association between both prestroke CHA₂DS₂-VASc score and the severity of stroke at presentation, as well as disability and mortality at 90 days, in patients with acute stroke and atrial fibrillation (AF). Methods This prospective study enrolled consecutive patients with acute ischemic stroke, AF, and assessment of prestroke CHA₂DS₂-VASc score. Severity of stroke was assessed on admission using the National Institutes of Health Stroke Scale (NIHSS) score (severe stroke: NIHSS ≥10). Disability and mortality at 90 days were assessed by the modified Rankin Scale (mRS <3 or ≥3). Multiple logistic regression was used to correlate prestroke CHA₂DS₂-VASc and severity of stroke, as well as disability and mortality at 90 days. Results Of the 1020 patients included in the analysis, 606 patients had an admission NIHSS score lower and 414 patients higher than 10. At 90 days, 510 patients had mRS ≥3. A linear correlation was found between the prestroke CHA₂DS₂-VASc score and severity of stroke (P = .001). On multivariate analysis, CHA₂DS₂-VASc score correlated with severity of stroke (P = .041) and adverse functional outcome (mRS ≥3) (P = .001). A logistic regression with the receiver operating characteristic graph procedure (C-statistics) evidenced an area under the curve of .60 (P = .0001) for severe stroke. Furthermore, a correlation was found between prestroke CHA₂DS₂-VASc score and lesion size. Conclusions In patients with AF, in addition to the risk of stroke, a high CHA₂DS₂-VASc score was independently associated with both stroke severity at onset and disability and mortality at 90 days.