Evidence suggests that vascular and inflammatory factors may be important in the etiology of Alzheimer disease (AD). The Glu/Glu genotype at the Glu298Asp variant of the endothelial nitric oxide synthase (NOS3) gene has been tested for association with AD in several Caucasian and Asian populations, with conflicting results. We tested the Glu298Asp variant for association in African American and Caucasian AD patients, unaffected siblings, and unrelated controls from the MIRAGE Study. To explore whether the inconsistent results in previous studies might be due to linkage disequilibrium with a polymorphism or haplotype not previously tested, we genotyped 10 additional NOS3 single nucleotide polymorphisms (SNPs) spanning 25.3 kb. Finally, we compiled results of previous studies of Glu298Asp using meta-analysis, to determine whether the aggregate studies support an association between Glu298Asp and AD. We found that the Glu298 allele was associated with higher risk of AD in the MIRAGE African American (p = 0.002) but not Caucasian (p = 0.9) groups. None of the additional SNPs were associated with AD in the Caucasians, whereas two showed evidence for association in the African Americans. The meta-analysis showed a small effect of the Glu298Asp GG genotype on AD risk across all studies (summary odds ratio = 1.15, 95% confidence interval: 0.97–1.35) and significant heterogeneity of this association among studies (p = 0.02).