The Na+/Ca2+ exchanger (NCX) is a membrane protein involved in calcium homeostasis, catalyzing the exchange of one Ca2+ ion for three Na+ ions across the cell membrane. The Na+/Ca2+ exchange has been suggested to play a role in the pathogenesis of hypertension. Therefore, we examined whether genetic variations in NCX1 were associated with hypertension. Among 15 polymorphisms identified in 96 hypertensive subjects by sequencing the entire exon and promoter regions of NCX1, 7 representative polymorphisms with a minor allele frequency of greater than 4% were genotyped in 1,865 individuals, of whom 787 were hypertensive and 1,072 were normotensive. These subjects were residents of Suita City and were randomly selected as a population for the Suita cohort study. Multivariate logistic regression analysis performed after adjusting for age, body mass index, hyperlipidemia, diabetes mellitus, smoking, and drinking revealed that the -23200T>C and -23181T>C polymorphisms in the 5' upstream region of exon 1c were significantly associated with hypertension in men (-23200T>C: CC vs. TC+TT: odds ratio=0.61; 95% confidence intervals: 0.39 to 0.97; p =0.04) and in women (-23181T>C: CC vs. TC+TT: odds ratio=1.45; 95% confidence intervals: 1.04 to 2.02; p =0.03), respectively. Thus, our study suggests that NCX1 is one of the genes related to susceptibility to essential hypertension in the Japanese general population.