Background and Purpose-Combined antiplatelet agents may offer additive protection over single drugs after stroke. We investigated whether platelet activation is reduced under combined aspirin and clopidogrel compared with each drug alone. Methods-In a case-crossover study, 31 patients with previous atherothrombotic or lacunar stroke who were treated with aspirin (100 to 300 mg/d) received clopidogrel (75 mg/d) and both aspirin and clopidogrel for 4 weeks. Platelet function in whole blood was studied after each treatment period and in healthy control subjects to assess activation-dependent antigens CD62p and CD63 by flow cytometry and collagen/epinephrine (CEPI-CT) and collagen/ADP (CADP-CT) closure times with the platelet function analyzer PFA-100, which investigates platelet-related function under shear stress. Results-CD62p expression and CD63 expression were not different under the 3 treatment regimens. CD63 but not CD62p expression was lower in control subjects than in stroke patients regardless of the antiplatelet treatment (PϽ0.05). CEPI-CT was prolonged under aspirin and aspirin plus clopidogrel compared with clopidogrel monotherapy (PϽ0.0001). CADP-CT was longer under combination therapy than under aspirin (Pϭ0.0009) or clopidogrel (Pϭ0.0074) or in control subjects (Pϭ0.0010), mainly because of strong prolongation in a patient subgroup (28%). Conclusions-CD63 expression reflecting the release of platelet lysosomes is consistently increased after stroke and incompletely suppressed by treatment with aspirin, clopidogrel, or both. The strong prolongation of CADP-CT under combined aspirin and clopidogrel in a patient subgroup may indicate a lower risk of thrombosis but also a higher risk of hemorrhage. The predictive value of platelet activation parameters requires investigation in prospective studies. Key Words: inflammation Ⅲ platelet aggregation inhibitors Ⅲ platelets Ⅲ secondary prevention A ntiplatelet drugs are the treatment of choice for secondary prevention after cerebral ischemia of noncardioembolic origin. However, the efficacy of presently available drugs is limited. Compared with placebo, aspirin reduced the relative risk of vascular events by 13% according to two meta-analyses 1,2 and stroke risk by 18% in the European Stroke Prevention Study 2. 3 Under clopidogrel, the relative risk of a compound outcome cluster of stroke, myocardial infarction, and vascular death was marginally, although significantly, lower than under aspirin (Ϫ8.4%), whereas the risk reduction for stroke alone was not significant. 4 Aspirin inhibits platelet aggregation by inhibition of cyclooxygenase, whereas clopidogrel reduces platelet activation via ADP receptor-dependent pathways. On the basis of these different modes of action, it is an attractive concept that the combination of both drugs may have additive effects on platelet See Editorial Comment, page 854 inhibition. The combination of aspirin and clopidogrel or ticlopidine was shown to be a successful treatment strategy after coronary stenting and in unstable angi...