In some patients with severe hypothyroidism thyroxine replacement therapy precipitates or aggravates angina pectoris, whereas in other patients angina pectoris is ameliorated or even disappears. The reason for this paradox is unknown. It has been attributed either to reversible endocrine cardiomyopathy in the form of asymmetric septal hypertrophy (ASH) or reversible anatomical narrowing of the coronary arteries. The results of a recent investigation, in which myocardial performance was surveyed by radionuclide ventriculography throughout early thyroxine replacement therapy in severe hypothyroidism, were compatible with the presence of reversible coronary dysfunction rather than of ASH. The aim of the present investigation was to confirm these findings. In six severely hypothyroid patients, without echocardiographic evidence of ASH or evidence of concomitant coronary artery disease (CAD), exercise and redistribution tomographic myocardial thallium-201 imaging (SPECT) was performed before thyroxine replacement therapy and repeated after 10 days and again after 2 months during therapy. In four patients substantial regional perfusion defects were demonstrated after exercise that were normalized at rest both before, and in one subject also after 10 days, on thyroxine. With restoration of euthyroidism, exercise and redistribution SPECT were normal in every patient. Determination of exact confidence limits reveals that the proportional incidence of myocardial perfusion defects in hypothyroidism, indicating myocardial ischemia, will at least be 22% with 95% probability. Despite the relatively low specificity of SPECT it seems pertinent to conclude that impaired myocardial perfusion as assessed by SPECT probably is due to reversible coronary dysfunction inherent in the hypothyroid state, and that this is not an infrequent manifestation of severe hypothyroidism.