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The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa PlA1/A2 polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients.We studied two populations. In loco, we genotyped 140 hypertensive control individuals and 28 hypertensive patients with ischemic stroke. Furthermore, we performed an analysis of previously published data of 451 Sardinian hypertensive patients, already characterized and genotyped.Association analysis revealed that the PlA2 distribution was similar between hypertensive patients with and without stroke, but when considering a more homogeneous population of high-risk hypertensive patients, defined according to ESH/ESC 2003 guidelines, we observed that the frequency of the PlA2 allele was higher among stroke versus nonstroke patients (stroke, 46.4%; nonstroke, 22.6%; P = 0.01). The multiple regression analysis taking into account this polymorphism among other factors known to contribute to ischemic stroke confirmed the PlA2 allele as an additive risk factor for stroke (B = 0.986, Wald = 4.943, P < 0.03), increasing the risk of stroke by 2.9 (95% confidence interval = 1.23–6.85, P < 0.02). Similar results were obtained in the Sardinian population: in hypertensive patients with three or more risk factors, PlA2 increases the risk (odds ratio = 2.8, 95% confidence interval = 1.3–6.0, P < 0.001) and is an additive risk factor for stroke (B = 1.073, Wald = 6.920, P < 0.01).Our data suggest that the PlA2 polymorphism is a genetic determinant of ischemic stroke in a selected high-risk hypertensive population.