We compared the ability of separately measured intimal-medial thickness and atherosclerotic plaque to predict incident cardiovascular disease. American Indian men and women from the Strong Heart Study who were free of cardiovascular disease were evaluated with carotid ultrasound and cardiovascular disease risk factor assessment. End-diastolic intimal-medial thickness of the common carotid arteries was measured and averaged. Arterial mass (cross-sectional area) was calculated from intimal-medial thickness and end-diastolic diameter. Atherosclerosis was defined by focal plaque (discrete thickening >50% relative to the adjacent wall) and the number of carotid segments containing plaque (plaque score); 2441 participants (age 63±8 years) were followed-up for a mean of 7.7±2.8 years, during which time 495 experienced incident cardiovascular disease events. Time-to-event analyses were performed in groups stratified according to diabetes and hypertension status. Cardiovascular disease events were predicted by presence and extent of atherosclerosis in all groups; intima-medial thickness and arterial mass were only associated with outcomes when neither hypertension nor diabetes was present. Unequivocal evidence of atherosclerosis (plaque) and its extent (plaque score) are independently associated with incident cardiovascular disease events in individuals without preexisting cardiovascular disease regardless of diabetes and hypertension status. Hypertension-related increases in intima-media thickness and arterial mass appear to limit their use as measures of early or diffuse atherosclerosis and, hence, association with cardiovascular disease outcomes. These findings support the utility of separate assessment of focal atherosclerosis and intimal-medial thickness in epidemiological studies, trials, and risk stratification protocols.