The authors evaluated risk factors potentially associated with the development of popliteal artery atherosclerosis in a population-based study and compared them with factors linked to carotid wall intimal-medial thickness. The Atherosclerosis Risk in Communities (ARIC) Study is a longitudinal investigation of cardiovascular disease in 15,800 individuals. The present analyses are based on the baseline popliteal and carotid ultrasonography examination in 10,002 subjects conducted in 1987-1989. After adjustment for covariates, both carotid and popliteal intimal-medial thicknesses were strongly associated with male sex and age (p < 0.01), having a graded relation with increasing quartiles of plasma total cholesterol and low density lipoprotein cholesterol and with plasma triglycerides (women only for popliteal) (p < 0.01). An inverse correlation was noted between plasma high density lipoprotein cholesterol and carotid (p < 0.01) and popliteal (women only) (p < 0.05) intimal-medial thicknesses. Cigarette use (p < 0.01), a history of diabetes mellitus (p < 0.01), alcohol use, elevated systolic pressures (p < 0.01), and fibrinogen levels (p < 0.01) were directly associated with both popliteal and carotid intimal-medial thicknesses. Although menopause was associated with thickened carotid (p < 0.01) and popliteal (p < 0.05) intimal-medial thicknesses, hormone replacement therapy was associated with thinner carotid walls only (p < 0.05). Although there were some differences, many of the classical risk factors associated with cardiovascular disease were also related to early thickening of both the popliteal and the carotid artery walls.