The functional morphology of the endothelial cells (ECs) covering advanced but uncomplicated sclerotic plaques in humans was studied in carotid endarterectomy specimens and in coronary arteries from hearts explanted because of advanced ischemic heart disease. The endothelial layer was nearly always intact, and the endothelial patterns reflected the anticipated local flow patterns along the narrowed arteries, with the majority of flow irregularities downstream from the stenosis. Large (giant) ECs (defined as ECs with a surface area of S800 fim 1 ) were frequently found on the plaque surface, probably indicating accelerated EC senescence attributable to sustained nondenuding injury in the region of disturbed flow. Ultrastructurally, activation of ECs with hyperplasia of organelles was frequent In addition, as a sign of immunological activation, about 5% of ECs express class II antigens (HLA-DR and rarely focal HLA-DQ), as demonstrated by double immunofluorescence with von Willebrand factor to identify the ECs. EC activation may be responsible for adherence to the intact luminal surface by activated platelets and monocytes, which were always present (in contrast with nonsclerotic artery segments). Furthermore, an increase in myo-endothelial contacts to subendothelial modified smooth muscle cells was a regular feature of the sclerotic lesions; this feature represents an unknown process of EC and smooth muscle cell interaction in the sclerotic lesion and may be a compensatory process for EC control of smooth muscle cell proliferation. In advanced plaques the ECs are altered without denudation but with changed properties, which may contribute to plaque growth and which are consistent with the postulated EC dysfunction in the pathogenesis of arteriosclerotic lesions. (Arteriosclerosis and Thrombosis 1991; 11:1678-1689)