The risk factor-gene interaction in carotid atherosclerosis was investigated in 205 community-dwelling healthy subjects aged 50 years or more in Japan. The intima-media thickness (IMT) of the common carotid artery was evaluated by ultrasonography with a 7.5-MHz probe. Gene polymorphisms were determined for each subject with angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT1R) A1166C, and apolipoprotein E (apoE) genotypes. There was no genotype-specific difference in carotid IMT among any genes examined. Combinations of genotypes did not increase carotid IMT compared with subjects without these genotypes. In the total population, multiple regression analysis showed that age, systolic blood pressure (SBP), sex, and body mass index (BMI) were significantly associated with carotid IMT. However, the association between risk factors and IMT was genotype-specific. Age was significantly associated with IMT in ACE D carriers, but not in subjects with the ACE II genotype. Analysis of covariance adjusted with other risk factors showed that the age-dependent change in IMT was significantly different between subjects with the ACE II genotype and the ACE D carriers (F[1.196] = 4.97; P = 0.027). Similarly, the regression of IMT on SBP was significantly different between AGT TT and AGT MT + MM (F[1.196] = 7.20; P = 0.0079). The regression of IMT on BMI was also significantly different between apo E4 carriers and noncarriers (F[1.196] = 6.78; P = 0.0099). Furthermore, general linear model analysis with risk factors, genotype, and risk factor-genotype interactions revealed that the age*ACE genotype interaction, the SBP*AGT genotype interaction, and the BMI*apoE genotype interaction were significantly associated with IMT. These findings further support the role of risk factor-gene interaction in carotid atherosclerosis.