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Introduction: Although platelet reactivity on clopidogrel is related to outcomes in patients with acute coronary syndromes, few studies have investigated its relation to clinical outcomes in acute ischemic stroke.Hypothesis: This study evaluated the association between clopidogrel resistance and early neurological outcomes in patients diagnosed with acute large artery atherosclerotic stroke.Methods: 1067 consecutive patients with onset within 7 days and stroke classification of large artery atherosclerosis were included. Platelet reactivity on clopidogrel was assessed using VeryfyNow P2Y12 assay at least 72 hours after the time of first clopidogrel dosage. Optimal cutoff value of clopidogrel resistance was obtained by using receiver-operating characteristic curve. Early neurological deterioration was defined as an increment of motor NIHSS score ≥1 before P2Y12 assay. We assessed any hemorrhagic transformation on 5-day MRI.Results: A total of 235 patients who met inclusion criteria were analyzed. The median initial dose of clopidogrel was 300 mg, and their median P2Y12 % inhibition was 26.3. P2Y12 % inhibition <29 was the significant discriminator of clopidogrel resistance with an AUC of 0.632 (95% CI 0.48-0.67; p=0.048). A multivariate analysis revealed that clopidogrel resistance is an independent risk factor even after adjustment for the variables that may affect the outcome (OR 2.75; 95% CI 1.11 to 6.83; p=0.029). Hemorrhagic transformation was not influenced by clopidogrel resistance (OR 0.60, 95% CI 0.14 to 2.540; P=0.484).Conclusion: In conclusion, high platelet reactivity with clopidogrel is an independent risk factor of early neurological worsening in acute large artery atherosclerotic stroke. Evaluation of ischemic stroke patients regarding antiplatelet resistance might be of clinical importance and alternative pharmacological strategies could be investigated in patients with high platelet reactivity.