In the atherosclerotic plaque, cycloxygenase-2 (COX-2) catalyzes prostaglandin E formation, which acts as a pro-atherogenic factor. A polymorphism, G/C −765, within the COX-2 promoter region modulates gene expression and the risk of cerebrovascular disease. We have evaluated the relation between COX-2 G/C −765 genotypes and the occurrence of cerebrovascular ischemia. We evaluated the COX-2 G/C −765 polymorphism in 110 consecutive patients with a documented history of acute ischemic cerebrovascular disease, in 110 age-matched and sex-matched subjects without such history, and in a general population (n = 324) from the same ethnical background. The frequency of the COX-2 −765C allele in patients [0.21; 95% confidence interval (CI), 0.16–0.26] was similar to those found in controls (0.28; 95% CI, 0.22–0.34) and in the general population (0.26; 95% CI, 0.23–0.29). Carriers of the CC genotype differed between patients (0.02; 95% CI, 0.00–0.05) and controls [0.10 (95% CI, 0.04–0.16), P = 0.019; odds ratio, 0.17 (95% CI, 0.04–0.79)] or the general population [0.08 (95% CI, 0.05–0.11), P = 0.023; odds ratio, 0.22 (95% CI, 0.05–0.95)]. In a multiple logistic regression analysis adjusted for confounding variables, smoking status (P < 0.001), atrial fibrillation (P = 0.004) and COX-2 G/C−765 polymorphism (P = 0.016) independently contributed to cerebrovascular ischemia, with CC carriers exhibiting a lower risk (odds ratio, 0.07; 95% CI, 0.01–0.61). Our data show an association between the COX-2 G/C−765 gene polymorphism and cerebrovascular ischemia, suggesting that the COX-2 gene is a susceptibility locus for the risk of cerebrovascular ischemic disease.