Our objectives were to assess the comparative value of thallium-201 and technetium 99m sestamibi for the detection of cardiac allograft atherosclerosis and the left ventricular ejection fraction response to exercise in heart transplant recipients with and without allograft atherosclerosis. Allograft atherosclerosis is the critical factor limiting long-term survival in heart transplant recipients. Annual coronary angiography is invasive and expensive. A noninvasive test to detect allograft atherosclerosis would be clinically useful. Treadmill exercise testing followed by myocardial perfusion single-photon computed tomographic imaging was performed in 25 heart transplant recipients. All patients underwent coronary angiography. Group 1 (13 patients) had angiographic coronary artery disease; group 2 (12 patients) did not. Eighteen patients underwent two exercise tests to equivalent work loads with thallium-201 and technetium 99m sestamibi; seven patients underwent only thallium-201 imaging. First-pass left ventricular ejection fraction was measured during injection of technetium 99m sestamibi. In group 1, 10 of 13 patients had abnormal thallium-201 scans. There was no significant difference in the number of patients who had abnormal thallium-201 (7/10) and technetium 99m sestamibi scans (6/10). Fifty-two percent (12/23) of discordantly scored segments were reversible on thallium-201 and fixed on technetium 99m sestamibi imaging compared with the opposite (0%; 0/23) (p < 0.01). All patients in group 2 had normal perfusion scans. There were no false-positive scans.(ABSTRACT TRUNCATED AT 250 WORDS)