To identify microanatomic and chemical features that may mark the transition from asymptomatic to symptomatic atherosclerotic carotid lesions, we evaluated 62 carotid artery bifurcation plaques including 45 high-grade stenoses removed at endarterectomy and 17 nonstenotic plaques recovered at autopsy. Morphologic features were evaluated on multiple-interval histologic sections and were graded for the presence of hemorrhage, ulceration, thrombosis, lumen surface irregularity, and calcification. Plaque hemorrhage, recent and remote, was found in most of the specimens, and did not discriminate between symptomatic and asymptomatic stenotic plaques. High-grade carotid stenotic plaques were associated with a significantly higher incidence of ulceration (53%), thrombosis (49%), and lumen irregularity (78%) when compared to nonstenotic asymptomatic plaques (6%, 0%, and 17%, respectively; p less than 0.01). Although these features were more prominent in lesions that produced symptoms, they were present in 80% of the stenotic bifurcations, and did not distinguish between symptomatic and asymptomatic endarterectomy plaques. No significant differences were found between symptomatic and asymptomatic high-grade lesions with respect to collagen, DNA, total cholesterol, fibrinogen, lipase, elastase, or collagenase content. We conclude that intraplaque hemorrhage is commonly seen in carotid plaques even without severe stenosis, and it does not appear to be a dominant determinant of symptoms. Ulceration and surface thrombi that may lead to cerebral embolization are prominent features in markedly stenotic plaques even when symptoms are absent. The disruptive processes that underlie plaque instability appear to be closely associated with plaque size and stenosis rather than plaque composition.