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Noninvasive measures of atherosclerosis, such as carotid intima-media thickness, total carotid plaque area, and carotid stenosis, probably represent different phenotypes with distinct determinants. For instance, total carotid plaque area may reflect atherosclerotic lesion size more closely than carotid stenosis, which instead may reflect hemodynamic compromise within the arterial lumen.In 1821 patients from a Premature Atherosclerosis Clinic, we studied determinants of total carotid plaque area and carotid stenosis as measured by ultrasound using multivariate regression analysis with traditional risk factors and some emerging risk factors.Regression modeling showed that (1) traditional atherosclerosis risk factors were more strongly associated with total carotid plaque area than with carotid stenosis (R =0.53 and 0.13, respectively), and (2) individual risk factors had different relationships with total carotid plaque area and carotid stenosis. For instance, age accounted for 53% and 26% of the explained variance of total carotid plaque area and carotid stenosis, respectively. Female sex was inversely associated with total carotid plaque area but positively associated with carotid stenosis. Nontraditional risk variables such as plasma homocysteine had different associations with the 2 analytes.Total carotid plaque area and carotid stenosis had different associations with specific atherosclerosis risk factors. Thus, for future studies of the determinants of atherosclerosis, it is important to distinguish between different phenotypes and to appreciate that they will not necessarily have the same determinants.