Previous reports suggest that low-density lipoprotein cholesterol (LDLc) is associated with atherosclerosis plaque initiation while cigarette smoking is more associated with plaque progression. The role of diabetes in plaque initiation and progression is not clear. The aim of this study was to confirm and extend these findings. Among 6384 men and women aged 45-84 free of clinical cardiovascular disease, subclinical atherosclerosis severity was classified on the basis of ultrasound measures of carotid stenosis and thickness and the ankle-brachial blood pressure index of lower extremity arterial disease. Carotid plaques were classified as echolucent or echogenic. Distensibility was calculated from the change in carotid diameter over the cardiac cycle. The smoking association with minimal, moderate, and more severe disease was progressive, estimated as equivalent to LDLc effects of 40, 85 and 238 mg/dl respectively. LDLc was relatively more associated with echolucent plaques; smoking with echogenic plaques. Diabetes was associated with carotid stiffness, whereas smoking was associated with greater distensibility. The results, together with pathological literature, suggest that LDLc may be of key importance both in plaque initiation and vulnerability to rupture, whereas smoking may relate to plaque progression to thicker, more fibrous lesions. Diabetes contributes uniquely to arterial stiffness.