Accelerated coronary artery disease is a common complication following orthotopic cardiac transplantation. The relationship between acute rejection and accelerated coronary artery disease remains unclear. While thallium-201 (201Tl) imaging has been advocated in the diagnosis of post-transplant coronary arteriopathy, other investigators have found little role for this technique in the evaluation of such patients. We undertook a retrospective review of 13 stress/rest (10 exercise, 2 dobutamine, 1 dipyridamole) and 2 rest/rest 201Tl single photon emission tomographic (SPET) imaging studies performed in seven patients post-cardiac transplantation (mean duration post transplantation = 2.5 years). Four of these patients had serial studies with an average interval between studies of 8.3 months (range 3-14 months). Coronary angiography was performed within 12 months of each 201Tl study (mean = 4.2 months). Using the coronary angiographic diagnostic criterion of ≥ 50% stenosis in one or more vessels, one or more fixed or reversible segmental defects were found on 201Tl imaging with a sensitivity of 78% and specificity of 33%. When the angiographic criterion of > 70% stenosis in one or more vessels was used the sensitivity increased to 100%, and where reversible segments were diagnostic the sensitivity was 67% and the specificity ranged from 42 to 58%. Although based on a small sample of patients, these results suggest that use of appropriate test methods and interpretive criteria may improve the utility of 201Tl SPET myocardial imaging in the diagnosis of coronary artery disease in cardiac transplant patients. Limited specificity may reflect associated pathological processes in these patients, including rejection, oedema and focal inflammation.