OBJECTIVE The purpose of this study was a head-to-head comparison of tomographic imaging (SPECT) with technetium-99m (Tc-99m)-sestamibi and thallium-201 (Tl-201) using dipyridamole-low-level bicycle exercise stress for the assessment of coronary artery disease. METHODS We studied 38 consecutive patients referred for the evaluation of chest pain who had undergone coronary angiography. The patients were randomly allocated to Tc-99m-sestamibi SPECT followed by Tl-201 SPECT or vice versa. The accuracy of both tracers in detecting significant coronary artery disease (> 50% luminal stenosis) was 87% (95% confidence interval 72-96%). Only two patients were classified differently by the two methods. RESULTS On a segmental basis, good agreement was found between Tc-99m-sestamibi and Tl-201 for both the localization and the nature of perfusion defects (reversible or persistent) identified (Cohen's kappa = 0.67). CONCLUSIONS No clinically relevant differences in diagnostic accuracy were demonstrated between Tc-99m-sestamibi and Tl-201 SPECT using combined dipyridamole-exercise stress for the evaluation of coronary artery disease.