Radiation therapy is a common therapeutic modality for several types of malignancy and causes a wide spectrum of cardiac disease. The ischemic heart disease associated with radiation exposure is most often due to increased atherosclerosis in epicardial arteries; another recognized mechanism, although less extensively described, is small intramyocardial vessel thickening without typical atherosclerotic changes. A 63-year-old male with chronic obstructive pulmonary disease and hypertension presented with the abrupt onset of epigastric discomfort and shortness of breath. He had been diagnosed with a localized 5 cm thoracic squamous cell carcinoma of the esophagus four years previously, and had been treated with five courses of 5-fluorouracil and cisplatin and six weeks of thoracic radiation therapy. He had remained in remission since that time. Lab work and electrocardiogram on presentation were unremarkable, but his shortness of breath progressed. He eventually required intubation for hypoxemia. With medical therapy he rapidly improved and was extubated, but required reintubation soon after. Further evaluation, including duplex Doppler sonograms of the lower extremities, CT of the head, and fiberoptic bronchoscopy, were nondiagnostic. Over the course of the next two days he developed acute renal failure and pulmonary edema refractory to medical therapy. Successive electrocardiograms showed progressive deep T-wave inversions in anterior precordial leads and T-wave alternans. Five days following admission the patient developed persistent hypotension and expired. Autopsy revealed intimal thickening and luminal narrowing of small intramyocardial arteries, widespread myocardial fibrosis and recent infarcts of the anterior and posterior papillary muscles, but no evidence of significant epicardial coronary disease. Although the association between epicardial coronary heart disease and radiation exposure is apparent, the true prevalence of small vessel disease is unclear. It may be that small vessel disease related to long-term effects of radiation injury contributes to the marked increase in ischemia; the actual burden of disease can only be elucidated by complete pathologic descriptions of patients with ischemic heart disease and a history of radiation exposure.