BACKGROUND: Platelet activation is an important process of atherothrombosis. However, there are few studies demonstrating the serial changes of platelet activation and the influences of the kinds of therapeutic strategies in atherosclerotic ischemic stroke from acute onset to the subacute phase. METHODS: We serially measured the expressions of CD63 on platelets in patients with atherosclerotic ischemic stroke (n=29) and compared them with normal subjects (n=52) and analyzed the effects to reduce the platelet activation according to the therapeutic strategies. RESULTS: The platelet CD63 expression (p<0.001) in atherosclerotic ischemic stroke significantly increased at 24 hours of ischemic stroke onset compared to normal subjects and their increment continually remained until 90 days after the ischemic events. Among the 29 patients, 12 patients treated with clopidogrel and aspirin showed significant decreases of the platelet CD63 expression (p=0.01) at 7 days compared to that at 24 hours. However, the reducing effect of this combination regimen disappeared after 90 days. CONCLUSIONS: These results suggest that the hyperexpression of CD63 on platelets in atherosclerotic ischemic stroke is not easily suppressed by regular anti-platelet medications.