BACKGROUND AND PURPOSE: Vasospasm after aneurysmal subarachnoid hemorrhage (SAH) remains a leading cause of death and disability after aneurysm rupture. Decreased availability of nitric oxide (NO) may be crucial in its pathogenesis. We hypothesized that endothelial NO synthase (eNOS) polymorphisms may determine susceptibility to vasospasm in SAH patients. METHODS: We conducted a prospective cohort study of SAH patients and determined vasospasm by cerebral angiography. We genotyped 3 eNOS polymorphisms: an intron 4 variable-number tandem-repeat, a promoter single-nucleotide polymorphism (-786T–>C SNP), and a coding SNP in exon 7 (894G–>T encoding E298D). Using multivariable logistic regression, we quantified the association of eNOS polymorphisms in patients with vasospasm confirmed by cerebral angiography. RESULTS: For the eNOS promoter -786T–>C SNP, the presence of the CC genotype compared with any T genotype (CT or TT) was associated with increased odds of vasospasm (odds ratio=2.97, 95% CI=1.32 to 6.67, P=0.008). No association with vasospasm was observed for the eNOS 894G–>T or variable-number tandem-repeat polymorphisms. CONCLUSIONS: These findings suggest that genetic variation influencing NO regulation contributes to the risk of angiographic vasospasm in patients with SAH. The specific role of the promoter SNP (-786T–>C) may determine the effect of NO regulated by this pathway, distinct from other known eNOS polymorphisms.