Background: Polymorphisms of the renin-angiotensin system are associated with cardiovascular pathology. Therefore, the association of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene and the T235 (methionine to threonine substitution) polymorphism of the angiotensinogen (AGT) gene with intima-media thickness of the carotid artery was investigated. Methods and results: Subjects were randomly selected from two centers participating in both the Atherosclerosis Risk in Communities (ARIC) and NHLBI Family Heart Studies. Probands were 45-64 years of age who were free of cardiovascular disease and had B-mode ultrasound measured carotid intima-media thickness. Multiplex polymerase chain reaction amplification was used to evaluate the ACE I/D and AGT T235 polymorphisms: genotype information was available on 495 and 475 participants, respectively. The frequencies of the ACE D and AGT T alleles were 0.56 and 0.52, respectively; 30% were homozygous for the ACE D allele, and 29% were homozygous for the AGT T allele. After adjustment for systolic blood pressure, antihypertensive medication use, diabetes, age, sex and LDL cholesterol, the mean intima-media thickness was 0.729, 0.732 and 0.721 mm in the ACE DD, ID, and II genotypes, respectively (partial F test 1.53, P = 0.22), and 0.727, 0.732 and 0.724 mm in the AGT MM, MT, and TT genotypes, respectively (partial F test 0.91, P = 0.40). Combining the genotypes for ACE and AGT, there were also no differences in intima-media thickness across the eight joint genotypes. Conclusion: We found no evidence that the ACE I/D and AGT T235 polymorphisms of the renin-angiotensin system were associated with carotid intima-media thickness in this population-based sample of middle- aged adults with no history of cardiovascular disease. The lack of an association between these variants and intima-media thickness may indicate that early atherosclerosis is mediated by factors other than these RAS polymorphisms.