The metabolic syndrome is associated with increased risk of cardiovascular disease. However, the association between metabolic syndrome and atherosclerosis in hypercholesterolemic patients remains unknown. We examined the association between carotid atherosclerosis and metabolic syndrome definitions using the NCEP-ATPIII, International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) definitions in 1782 subjects at risk of cardiovascular disease including 926 with hypercholesterolemia (LDL cholesterol >/=160mg/dL; mean=203mg/dL). Irrespective of definition, carotid intima-media thickness was significantly higher in both men and women diagnosed with the MetS compared to those without MetS. This relationship persists in males with hypercholesterolemia, independently of LDL cholesterol level. Regression analyses, both unadjusted and adjusted for traditional risk factors, indicate that in males the AHA/NHLBI definition, and in females the IDF definition are the strongest predictors of carotid atherosclerosis. These results highlight important gender differences that exist in the current clinical definitions of the metabolic syndrome, with regards to predicting early atherosclerotic lesions. In addition, this study shows that in males with hypercholesterolemia, MetS is independently associated with increased atherosclerosis, supporting screening for MetS among people at risk of CVD.