Recurrent carotid stenosis occurs randomly in approximately 10% of patients undergoing endarterectomy. Previous studies have described several histologic features but have failed to clearly elucidate the pathogenesis of this disorder. To improve our understanding of this disease, we reviewed pathologic lesions from 20 patients with recurrent stenosis. All specimens had been fixed in formalin and were embedded in paraffin and had undergone routine microscopic studies. In addition, immunoperoxidase staining with anti-factor VIII for endothelial cells and anti-desmin and anti-actin for smooth muscle cells was performed. Recurrent stenosis had developed in 16 of the 20 specimens within 2 years of endarterectomy (early), whereas the remaining four cases occurred from 2 to 7 years after the original carotid endarterectomy (late). Endothelial cells were found lining the luminal surface of both early and late recurrent lesions. Six of sixteen early and three of four late specimens had areas of luminal surface covered with cells exhibiting immunoreactivity for anti-factor VIII. Cells showing immunoreactivity for actin or desmin and demonstrating the morphology of smooth muscle cells were found in 9 of 16 early restenotic lesions but in no late ones. Areas of endothelial cell lining of the recurrent carotid lesions in a substantial number of patients in this study represent a finding not previously described. The presence of these cells implies that a phase of the arterial healing after endarterectomy involves re-endothelialization. Contrary to previous reports, no significant role of thrombosis and/or intraplaque hemorrhage could be found to contribute to development of recurrent stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)