Human essential hypertension has a multifactorial origin and is caused by a delicate interaction between susceptibility genes and environmental factors. Candidate genes are selected from the renin-angiotensin system (RAS) and are physiologically implicated in blood pressure regulation. We investigated the association between insertion/deletion (I/D) polymorphism at the angiotensin-converting enzyme (ACE) locus and hypertension in a case-control study conducted in a population of Caucasians (175 females, 210 males). Case subjects were those with untreated borderline hypertension. A significant, moderate, male, gender-specific independent association between DD genotype and high blood pressure was found. Adjusted odds ratio (OR) was 2.0 (95% CI, 1.1 to 3.9; p=0.03) in the whole group and 2.5 (95% CI, 1.2 to 5.1; p=0.01) in the group truncated on the basis of age (< or = 50 years). Our findings support the hypothesis that ACE is a gender-specific candidate gene for hypertension.