eNOS (endothelial NO synthase) plays a critical role in the development of ventricular remodelling and cardiac hypertrophy. The purpose of the present study was to determine whether three common variants in NOS3 (the eNOS gene) are associated with the risk of LVH [LV (left ventricular) hypertrophy] in patients with essential hypertension. Three NOS3 genetic variants, -T786C (rs2070744), eNOS4a/b and +G894T (rs1799983), were genotyped in two independent case-control studies: the first study consisted of 1061 hypertensive patients with LVH and 1118 hypertensive patients without LVH, and the second sample consisted of 120 patients with LVH and 223 patients without LVH. Echocardiographic measurements were obtained in all of the hypertensive patients. Only the +G894T (E298D) variant of NOS3 was associated with a higher risk of LVH {OR (odds ratio), 1.67 [95% CI (confidence interval), 1.19-2.36]; P<0.01} in the first population, and replicated in the second population [OR, 1.41 (95% CI, 1.01-2.28); P<0.05] in a recessive model. Compared with carriers of the G allele (GT+GG), patients carrying the TT genotype had increased septal wall thickness (16.2%, P<0.01 and 11.7%, P<0.01 respectively), LV posterior wall thickness (8.3%, P<0.01 and 7.1%, P<0.01 respectively), LV mass index (14.0%, P<0.01 and 25.1%, P<0.01 respectively) and relative wall thickness (13.1%, P<0.01 and 16.2%, P<0.01 respectively) in the first and second populations. The results of the present study support that homozygosity for +G894T (E298D) in NOS3 is a genetic risk factor for the development of LVH in patients with hypertension.