Background. Pharmacologic stress has been shown in animal studies to induce high degrees of myocardial hyperemia. At these levels of myocardial blood flow, the myocardial uptake of technetium 99m sestamibi may plateau and may affect the diagnostic accuracy, This study compared the effects of myocardial hyperemia induced by exercise, dipyridamole, and adenosine on Tc-99m sestamibi tomographic imaging in normal subjects and patients with ischemic coronary artery disease. Methods and Results. Twenty subjects (group I, 10 normal subjects; group II, 10 patients with known coronary artery disease) underwent Tc-99m sestamibi tomographic imaging after rest, exercise, dipyridamole infusion, and adenosine infusions on separate occasions. Total and background-corrected myocardial counts of the resulting images were calculated. Visual and computer-generated quantitative myocardial perfusion defect analysis was performed in subjects in group II. For subjects in both groups I and II, there were no significant differences in the background-corrected myocardial counts obtained with exercise, dipyridamole, and adenosine stress. There were no significant differences in the myocardial perfusion defects obtained after the three different modes of stress, including percentage defect size, stress deficit percentage, percentage of ischemia, count deficit index, and defect nadir. Conclusions. The myocardial uptake of Tc-99m sestamibi in normal subjects and patients with coronary artery disease is comparable after exercise, dipyridamole, and adenosine stress. In addition, the defect sizes and intensities with Tc-99m sestamibi after all forms of stress were equivalent. Thus Tc-99m sestamibi, in combination with either adenosine or dipyridamole infusions, provides imaging data equivalent to those with exercise and may be considered an alternative in patients unable to undergo adequate exercise.