High blood pressure is a predictor of cardiovascular disease. Hence, genes contributing to essential hypertension may play a role in the etiology of cardiovascular disease. For this reason, we examined the association between the &agr;-adducin (ADD1) G460W and G-protein &bgr;3 subunit (GNB3) 825C>T polymorphisms and the prevalence of peripheral arterial disease (PAD) and incidence of coronary heart disease (CHD) in non-Hispanic whites from the Atherosclerosis Risk in Communities (ARIC) Study. PAD prevalence was defined by an ankle-brachial index, ie, the ratio of ankle systolic blood pressure to brachial artery systolic blood pressure, of ≤0.90 for men and ≤0.85 for women. CHD incidence was determined by following the ARIC cohort for a median of 5.3 years for potential coronary events. Stratified random samples of the ARIC cohort (n=703 and n=684) were used, respectively, as the comparison groups for the PAD (n=144) and incident CHD (n=408) cases. TheGNB3825T allele and theADD1460W allele were not significantly associated with prevalence of PAD or incidence of CHD. However, a test of the interaction between hypertension status and theADD1G460W polymorphism indicated that further evaluation of theADD1polymorphism in only hypertensive individuals was warranted. TheADD1460W allele was significantly associated with PAD (odds ratio [OR]: 2.61, 95% CI, 1.27–5.37,P=0.01) and CHD (hazard rate ratio [HRR]: 2.30, 95% CI, 1.20–4.42,P=0.01) in hypertensive individuals after adjustment for multiple cardiovascular disease risk factors. An interaction with hypertension in the association between theADD1G460W polymorphism and cardiovascular disease merits further testing in additional populations.