Mediastinal irradiation can induce coronary artery disease characterized by fibrous lesions developing in the absence of lipid/foam cell accumulation. We document several consecutive cases of acute coronary artery occlusion developing over radiation-induced lesions in patients who were relatively young, without evidence of classical risk factors for atherosclerosis, and in whom the coronary vasculature was otherwise apparently free of disease. The finding of acute coronary artery occlusion at the site of a fibrous lesion lends further support to the hypothesis that acute coronary syndromes may not necessarily be identifiable with ulceration/disruption of the atherosclerotic plaque as the underlying mechanism of acute thrombus formation.