To assess the prevalence of chest pain and ischemic electrocardiographic (ECG) changes and relate them to histopathologic findings of coronary arteries in cardiac amyloidosis, 33 patients with AL (primary) amyloidosis and 60 patients with familial amyloid polyneuropathy (FAP) were examined. Five patients (15%) with AL amyloidosis had recurrent anginal pain with exertion and 2 of them also experienced anginal pain after orthostatic hypotension. The chest pain was associated with transient downsloping or horizontal ST-segment depression with or without T-wave inversion in right precordial leads, whereas the remaining patients with AL amyloidosis and all patients with FAP did not show anginal pain or ischemic ST-T changes. Histologic sections of coronary arteries were obtained in 12 patients with AL amyloidosis, including 4 of the 5 patients who had angina pectaris and in 25 patients with FAP. Three patients with anginal pain had variable degrees of stenoses of the intramural coronary arteries by amyloid deposition predominantly in the media with normal or nearly normal epicardial arteries. One patient with AL amyloidosis who had effort angina showed marked stenosis and complete occlusion of the small coronary vessels by transmural amyloid deposition. The remaining 8 patients with AL amyloidosis and 25 with FAP without chest pain did not exhibit any stenosis or occlusion of both the epicardial and intramural vessels. These findings suggest that ischemic ST-T changes with chest pain are not so rare in patients with AL amyloidosis, and that markedly decreased myocardial oxygen supply due to diffuse stenotic or occlusive disease of the small coronary vessels by amyloid deposition contributes to the development of clinically significant ischemic heart disease in these patients.