We examined whether vascular endothelial growth factor (VEGF) polymorphisms (C-2578A, G-1154A and G-634C) are associated with hypertension, response to antihypertensive therapy and nitric oxide (NO) formation. Substudy 1 compared the distribution of VEGF genotypes and haplotypes in 178 patients with arterial hypertension (100 whites and 78 blacks) and 186 healthy controls (115 whites and 71 blacks). Substudy 2 compared the distribution of VEGF markers in 82 patients with controlled hypertension, 89 patients with resistant hypertension and 101 normotensive (NT) patients. In substudy 3, plasma nitrite/nitrate (NOx) levels were determined (chemiluminescence assay) in 64 NT subjects and 48 hypertensive (HTN) subjects, and the distribution of VEGF markers was compared in subjects having low NOx with subjects having high NOx. Although the substudy 1 showed no differences in genotypes or allele distributions for the three VEGF polymorphisms between NT and HTN subjects, the 'C-A-G' haplotype was more common in white NT subjects than in the white HTN subjects, and the 'C-A-C' haplotype was more frequent in black and white HTN subjects than in black and white NT subjects. The substudy 2 showed similar results, with no differences between responsive and resistant HTN subjects. The substudy 3 showed that the 'C-A-G' haplotype, which had a protective effect against hypertension, was significantly more common in subjects with higher NOx concentrations than in subjects with lower NOx concentrations. VEGF haplotypes are associated with hypertension, and the haplotype associated with normotension was more common in subjects with increased NO formation, possibly offering a mechanistic clue for our findings.