Background and Purpose— Ischemic stroke (IS) is a complex disease that involves genetic and environmental factors. In a family-based study (the Genetic Analysis of Idiopathic Thrombophilia [GAIT] Project) that included a genome-wide scan, we demonstrated that a common polymorphism (46 C→T) in the exon 1 of the F12 gene jointly influences variability of plasma Factor XII levels and susceptibility to thrombotic disease. We have investigated the risk of IS related to this polymorphism in a case–control study. Methods— We studied 436 individuals: 205 diagnosed with IS and 231 age–gender–ethnic control subjects. We measured Factor VIIIc, fibrinogen, and Factor XIIc levels, and we genotyped the 46 C→T polymorphism in the F12 gene. Results— There were 91 women and 114 men in the IS group and 109 women and 122 men in the control group. We confirmed our previous observation that individuals with different genotypes for the 46 C→T polymorphism showed significant differences in Factor XIIc levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T ) was associated with an increased risk of IS with an adjusted odds ratio of 4.1 (95% CI, 1.1 to 15.9). Conclusions— This study suggests that the 46 C→T polymorphism is a genetic risk factor for IS in the Spanish population. In addition, our results confirm that the use of genetic linkage studies along with a case–control association study is an extremely valuable approach for identifying DNA variants that affect complex diseases.