The insertion/deletion (I/D) polymorphism of the human angiotensin-converting enzyme (ACE) gene is a major determinant of circulating ACE activity, with the D allele being associated with higher ACE levels than the I allele. Thus, chronic exposure to high levels of circulating and tissue ACE may well predispose to vascular wall thickening and atherosclerosis. However, the effect of the ACE gene on carotid atherosclerosis remains controversial. We investigated the association between ACE gene I/D polymorphism and risk factor-dependent augmentation of carotid arterial remodeling in subjects with several risk factors for atherosclerosis. We evaluated sclerotic lesions of the common carotid artery with intima-media thickness (IMT) by ultrasonography in 184 patients (mean age +/- SD, 67 +/- 14 years old) and studied whether any risk factor-gene interactions were associated with carotid atherosclerosis. Out of the 184 subjects, 71 had the ACE II genotype, 87 the ID genotype and 26 the DD genotype. There was no significant difference in IMT among the three ACE genotypes. In total subjects, multiple regression analysis showed that age, total-cholesterol (T-C), and HDL-cholesterol (HDL-C) were significantly associated with IMT. However, the association between risk factors and IMT was genotype-specific. Systolic blood pressure (SBP) and HDL-C were significantly associated with IMT in ACE D carriers (DD+ID), but not in subjects with the ACE II genotype. Similarly, T-C was significantly associated with IMT only in subjects with the ACE II genotype. A general linear model of the interaction between the ACE genotype and the conventional risk factors showed that the SBP-ACE genotype interaction were significantly associated with IMT (F = 7.915; p = 0.005). This finding further supports the idea that analysis of risk factor-gene interaction could be a useful tool for deriving specific predictive information about the development of atherosclerosis.