Although several studies of molecular genetics have investigated the relevance of the ACE gene to essential hypertension, the relationship remains controversial. Some studies have recently implicated sex-specificity of this candidate gene in hypertension genetics; that is, significant linkage and association were observed in men but not in women in Caucasian populations. In particular, a male-specific association was seen between the ACE insertion/deletion (I/D) polymorphism and hypertension. This could partially explain the negative results for such an association in a number of previous studies in which the subjects were not stratified according to sex. To determine whether the ACE I/D polymorphism is related to essential hypertension in Japanese subjects, we conducted a case-control study in 701 men (387 hypertensive and 314 normotensive subjects) and 542 women (324 hypertensive and 218 normotensive subjects). The genotype distribution (or allele frequencies) and hypertension status were compared between the case and control subjects with the chi2 test statistic. We found no significant association between I/D genotype and hypertension when men and women were analyzed separately or together. The results did not change appreciably when the case group of each sex was subdivided according to more stringent criteria. The odds ratio for D-allele vs. I-allele was estimated to be 0.90 (95% CI; 0.73-1.12) in men and 0.90 (95% CI; 0.70-1.16) in women. Taken together, our data do not support the existence of a sex-specific association between the ACE I/D polymorphism and essential hypertension in the Japanese population.