During development of atherosclerotic lesions, vascular smooth muscle cells (SMCs) undergo changes both phenotypically and in their cytoskeleton composition. An expression of cytokeratins 8 and 18 in SMCs in plaques of the human superficial femoral artery and of cytokeratin 8 in lesions of the aorta was recently described. Since cytokeratins are epithelial markers generally not found in normal adult vascular SMCs, we performed a detailed immunofluorescence microscopy study using a large panel of antibodies against the various cytokeratin polypeptides and other elements of the cytoskeleton. We included lesions of carotid, common and superficial femoral, iliac, and popliteal arteries; the abdominal aorta; and saphenous vein bypass grafts, as well as primary, restenotic, and transplantation-associated lesions of coronary arteries (n=33). Cytokeratins 8 and 18 were present in myointimal cells of all pathological specimens. Colocalization with smooth muscle ix-actin identified most cytokeratin-positive cells as SMCs. Only very few cells cosynthesized cytokeratin and desmin, whereas the majority of cytokeratin-positive cells were vimentin-positive. This pattern of cytoskeletal protein synthesis is similar to that found in some fetal and/or neonatal SMCs. These findings suggest that the synthesis of cytokeratins in a subset of SMCs of atherosclerotic lesions is a common phenomenon in coronary artery and peripheral vascular disease as well as graft disease and transplantation-associated arteriosclerosis and that the state of these SMCs is of a "dedifferentiated" fetal type.