Diabetes mellitus (DM) and metabolic syndrome (MS) are associated with adverse cardiovascular outcomes. However, the extent and progression of coronary atherosclerosis for these conditions have not been directly compared. Three thousand four hundred fifty-nine patients with coronary artery disease underwent serial evaluation of atheroma burden by intravascular ultrasound. Patients with DM, MS, or neither diagnosis were compared with regard to plaque burden, progression, and arterial remodeling. Among the 3 groups, patients with MS had the largest number of individual cardiovascular risk factors. Patients with DM demonstrated more extensive atherosclerosis burden with a greater percent atheroma volume compared to patients with MS or those with neither diagnosis (40.3 +/- 9.0%, 37.6 +/- 8.9%, and 38.1 +/- 9.1%, p <0.001) and total atheroma volume (198.3 +/- 85.9, 190.7 +/- 85.0, and 186.3 +/- 79.1 mm(3), p = 0.05). MS compared to neither diagnosis was accompanied by expansion of the external elastic membrane (501.3 +/- 174.3 vs 484.4 +/- 160.7 mm(3), p = 0.02), whereas DM was associated with lumen constriction (290.6 +/- 111.7 vs 298.1 +/- 105.5 mm(3), p <0.0001). On serial evaluation, DM, but not MS, was associated with greater progression of percent atheroma volume compared to neither diagnosis (+0.8 +/- 0.3, +0.3 +/- 0.2, and +0.1 +/- 0.2%, p <0.0001) and total atheroma volume (-1.0 +/- 1.8, -3.3 +/- 1.8, and -4.0 +/- 1.8 mm(3), p = 0.001). Meeting criteria for MS was not associated with greater disease progression in patients with DM. In conclusion, despite having fewer individual risk factors, DM is associated with greater plaque progression and more constrictive remodeling than MS. This finding highlights the deleterious effects of DM on the arterial wall independent of its associated metabolic abnormalities.