Clopidogrel resistance causes recurrent stroke. However, outcomes of modified antiplatelet medications to prevent recurrent ischemic stroke are not well known. Patients who received clopidogrel with and without modification as initial treatment for stroke were recruited and compared. The primary outcome was ischemic stroke and myocardial infarction at the 1-year follow-up. The secondary outcome was bleeding complications. Overall, 206 patients treated with clopidogrel were enrolled and were divided into the modification (n = 39) and no modification (n = 167) groups. There was a significant difference in the incidence of severe cerebral arterial stenosis between the two groups (modification group, 16/39, 41.03%; no modification group, 36/167, 21.56%, P = 0.012) at baseline. The loss to follow-up rate was 12.14% (25/206). After adjustment for severe cerebral artery stenosis, antiplatelet modification based on the platelet reactivity unit (PRU) value significantly improved in the per protocol set (odds ratio 0.142, 95% confidential interval 0.022-0.898, P = 0.038). The area under the curve of the different PRU cutoff values were 0.630, 0.605, and 0.591 (P = 0.016, 0.051, and 0.092) for PRU 190, 208, and 235, respectively. Verifynow P2Y12 PRU-guided modification of clopidogrel for ischemic stroke significantly improved or prevented recurrence at the 1-year follow-up. Our findings suggest that clopidogrel therapy based on the PRU cutoff value of 190 should be considered to improve outcomes. ClinicalTrials.gov NCT02618265 (December 1, 2015).