Variations in plaque composition could make carotid artery plaques prone to ulceration, subintimal hemorrhage, plaque progression, or embolization and, thus, increase the risk of ipsilateral ischemic neurologic events. Seventy-eight carotid endarterectomy specimens from 74 patients (38 symptomatic and 36 asymptomatic) were analyzed. Prior to analysis, 43 of the 78 plaques were divided into sections based on disease severity and examined by light microscopy for surface ulceration and subintimal hemorrhage. Extracted lipid, cholesterol, collagen, and calcium content were determined in all 78 plaques and compared to clinical presentation and/or morphologic observations. Plaques removed from symptomatic patients contained more extracted lipid and cholesterol than those from asymptomatic patients. In addition, compared to the remainder of the plaque, the most stenotic portion of the plaque contained more cholesterol, more calcium, and less collagen. Finally, irrespective of clinical presentation, plaque sections found to have surface ulceration and subintimal hemorrhage contained more cholesterol and less collagen than plaques without these changes. Lipid-laden plaques with low levels of collagen are associated with plaque ulceration, subintimal hemorrhage, and ischemic neurologic symptoms. This suggests that plaque composition may be an important factor in the pathophysiology of carotid atherosclerosis.