Cytotoxicity mediated by cytolytic T cells occurs exclusively through Fas-and perforin-based pathways. Such mechanisms may be important in transplant coronary artery disease (TxCAD). We studied Fas and perforin expression and apoptosis using immunohistochemical methods, in situ terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL), and morphologic analysis of vessels with TxCAD taken from 12 transplant patients, which we compared with vessels of 10 patients with native coronary artery disease (CAD) and vessels from 14 patients with normal coronary arteries. Fas was detected in all TxCAD specimens. Fas-positive cells were mainly endothelial cells (EC); 100% of EC and approximately one-third of T cells and macrophages were positive for Fas. Almost all TUNEL-positive cells were Fas-expressing cells. Of the T cells and macrophages that expressed Fas, 18% appeared apoptotic in the mild and moderate-to-severe TxCAD group as compared with 78% in severe TxCAD patients (p= 0.0124). By contrast, EC damage was less evident in the vessels with greater intimal disease severity: 10% in severe TxCAD versus 75% in the mild and moderate-to-severe TxCAD group (p= 0.0122). Perforin was positive in 5% of the total intimal T cells in 3 of 12 arteriopathy specimens. Fas and perforin were virtually negative in vessels taken from CAD patients. TUNEL was diffusely positive in CD68-positive foam cells in the lipid-rich core, but Fas was negative in all CAD specimens. In normal arteries, 8 of 14 specimens contained a few TUNEL-positive and Fas-positive EC and T cells. Perforin was negative. We conclude that EC damage in TxCAD seems to be brought about through a Fas-based apoptotic pathway and that CD4-positive cytolytic T cells may be the major lytic cells involved in TxCAD.