Although the pathogenic mechanisms involved in predisposing individuals to hypertension are not well defined, evidence is accumulating that suggests a strong genetic transmission. Animal studies and some clinical investigations have revealed that aberrant NO production may be an important contributing factor. Indeed, a missense mutation in the endothelial NO gene caused by a Glu298Asp alteration has been strongly associated with essential hypertension, coronary artery spasm, and myocardial infarction. Recently, another point mutation caused by a T-786→C transition in the 5′-flanking region of the endothelial NO synthase gene has been identified and, like the Glu298Asp mutation, is associated with coronary artery spasm. The present study was conducted to determine the effect of the T-786→C point mutation on hypertension. We investigated the interaction between the endothelial NO synthase T-786→C polymorphism and blood pressure in a large (n=705) clinically healthy population. Allele frequencies for the T and C alleles were 62% and 38%, translating into 39%, 46% and 15% of the population having the T/T, T/C, and C/C genotypes, respectively, for the T-786→C point mutation. Subjects with the C/C genotype had significantly higher systolic blood pressures and were 2.16(95% confidence interval, 1.3 to 3.7) more likely to be hypertensive. Therefore, the −786 C/C genotype in NO synthase is a significant contributing factor for increasing the risk of essential hypertension.