It has been suggested that apoptosis contributes to the pathogenesis of atherosclerosis and to the instable plaque syndrome. The role of apoptosis in aorto-coronary venous graft occlusion is unknown. Therefore, we compared the occurrence of smooth muscle cell (SMC) apoptosis and apoptosis-related molecular markers in occluded vein grafts (CABG) with native coronary artery disease. Neointimal SMC of occluded CABG (n = 30) and desobliterates from occluded native coronary arteries (n = 65) were immunohistochemically stained in situ for the detection of p53, bax, bcl-2 and TUNEL (TdT-mediated dUTP-biotin nick endlabeling). The occurrence of apoptosis-promoting molecular markers and concomitant SMC apoptosis (% positive stained SMC ± SE) was significantly increased in occluded CABG compared to coronary artery desobliterates (p53: 6.8 ± 2.3 versus 0 p < 0.005; bax: 5.4 ± 1.5 versus 3.6 ± 0.9 p < 0.05; TUNEL: 3.8 ± 1.7 versus 1.1 ± 0.4 p < 0.05). SMC apoptosis is significantly increased in occluded venous grafts compared to primary coronary artery disease, and may play a role in the pathogenesis of vein graft disease. The documented increase in apoptosis-promoting molecular markers could be the basis for new therapeutic strategies for the prevention of venous graft occlusion.