Accumulating evidence strongly suggests that an alteration in nitric oxide metabolism is involved in the pathogenesis of hypertension. We recently found 2 polymorphisms in the endothelial nitric oxide synthase (eNOS) gene, a Glu298Asp missense variant in exon 7 and a T-786-->C variant in the 5'-flanking region, which are not linked to each other. In our previous reports, we showed a positive association between the Glu298Asp variant and essential hypertension, myocardial infarction, and coronary spastic angina. We also revealed that the T-786-->C variant is strongly associated with coronary spastic angina and leads to the reduction of the eNOS gene promoter activity. To further investigate the genetic involvement of the eNOS gene in essential hypertension, we examined the frequency of T-786-->C variant in two independent populations of persons with essential hypertension in Kyoto (n=215) and Kumamoto (n=186) and compared the frequency with that in each age- and gender-matched control (233 controls in Kyoto and 223 controls in Kumamoto). In both groups, the frequency of T-786-->C variant was similar in patients with hypertension and normal controls. In conclusion, the T-786-->C variant was not positively associated with essential hypertension. Given the evidence of positive association of another polymorphism in the eNOS gene, the Glu298Asp polymorphism, with essential hypertension, special attention will be required to interpret the results of a case-control study for genetic risk factors.