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Background and Purpose: Direct oral anticoagulants (DOACs) are widely used for the prevention of ischemic events with non-valvular atrial fibrillation (NVAF). However, it is unknown when DOACs should be started after acute ischemic stroke (AIS) or transient ischemic attack (TIA). The aim of this study was to compare the short- and long-term stroke outcomes between earlier initiation and later initiation of DOACs after onset of AIS.Methods: Patients with NVAF who developed AIS/TIA were enrolled from the database of the prospective, multicenter, observational SAMURAI-NVAF study, and they were divided into two groups according to the date of starting DOACs after stroke onset: within 3 days (E-group) and 4 or more days (L-group). The frequency of ischemic event, bleeding, and death up to 2 years was compared.Result: DOACs were started as the first oral anticoagulants after AIS/TIA in 499 (42%) of 1192 NVAF patients. Of these, 223 patients were assigned to E-group (74±6 years of age, 78 women) and 276 patients to L-group (75±6 years of age, 101 women). E-group had lower scores of National Institutes of Health Stroke Scale (median 3, interquartile range [IQR] 1-8 vs 5, 2-14; P=0.001) and CHAD2S-VASc (median 5, IQR, 4-6 vs 5, 4-6; P=0.04) than L-group. No significant difference was observed in the rate of ischemic events (at 3 months: E 4.0% vs L 2.5%, harzard ratio [HR] 1.59, 95% confidence interval [CI] 0.58-4.48; at 2 years: E 9.4% vs L 10.9%, 0.89, 0.50-1.56), bleeding (at 3 months: E 1.4% vs L 2.2%, HR 0.48, 95% CI 0.10-1.88; at 2 years: E 3.6% vs. L 4.0%, 0.97, 0.36-2.51), and death (at 3 months: E 0.5% vs L 0.4%, HR 1.22, 95% CI 0.05-31.52; at 2 years: E 4.5% vs L 8.7%, 0.57, 0.26-1.17) after multivariable adjustment.Conclusion: Early starting of DOACs within 3 days after the onset of AIS/TIA had comparable outcome to later starting of them regarding ischemic events, bleeding, and death.