This study represents a systematic analysis of the fine-structural characteristics of atherosclerotic lesions of the superficial femoral artery in man together with the growth characteristics in culture of the smooth muscle cells derived from these lesions. Occlusive fibrous atherosclerotic plaques were obtained from 29 male patients at the time of bypass surgery for occlusion of the superficial femoral artery and were studied by light and transmission electron microscopy. The occluded segment of each artery was obtained immediately after removal from the patient and examined with sterile techniques, and representative segments were fixed for light-and electron-microscopic study. Adjacent segments were used for dissection of the lesion away from the underlying media, and smooth muscle cells were cultured from lesion and nonlesion areas and compared in terms of their growth responses to increasing concentrations of a pool of human whole blood serum. The majority of the lesions were fibroproliferative and contained relatively little lipid. The fibrous cap that covered each lesion consisted of a special form of dense connective tissue that contained flat, pancake-shaped smooth muscle cells in a lacunalike space. This space consisted of concentric layers of basement membrane, collagen fibrils, and proteoglycan. The majority of the cells beneath the fibrous cap were smooth muscle cells mixed with small but varying numbers of macrophages. Most of the lesions were occluded by a thrombus, which had undergone organization and recanalization. A small number of the lesions had deep lipid deposits together with foci of degeneration and calcification. The occluded thrombi contained smooth muscle cells and a larger proportion of macrophages than the lesions themselves. The in vitro growth properties of the smooth muscle cells isolated from the lesion and the underlying media suggested that the lesion cells had senesced, compared with the medial smooth muscle cells derived from the same artery.