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Background: Transient Ischemic Attack (TIA) patients with acute Diffusion-Weighted Image (DWI) hyperintensities bear a high risk of a subsequent ischemic stroke. Few studies focused on the efficacy of dual antiplatelet therapy (DAPT), clopidogrel plus aspirin, in TIA patients with acute DWI hyperintensities. The study aimed to identify whether dual antiplatelet therapy could decrease early stroke risk after TIA with acute DWI lesion.Methods: Patients with a transient ischemic attack within 72 hours and acute DWI lesions, within the prospective TIA database from the First Affiliated Hospital of Zhengzhou University, were screened in the present study. Baseline characteristics including antiplatelet therapy during hospitalization were recorded. The relationship between DAPT and the 90-day stroke risk after the index TIA were analyzed in a Cox proportional hazards model to adjust confounding factors.Results: Overall, 270 TIA patients with acute DWI lesions were recruited in the present study.The 90-day stroke risk was 13.4% in patients with dual antiplatelet therapy compared with 23.6% in those with monotherapy (p=0.0491). Dual antiplatelet therapy was associated with reduced early stroke risk in TIA patients with DWI hyperintensities (HR, 0.53; 95% CI, 0.29-0.96) , after adjusting for confounding factors.Conclusions: Dual antiplatelet therapy reduced early stroke risk in TIA patients with acute DWI hyperintensities. Randomized controlled trials are needed to validate our results.