From a consecutive series of patients who underwent rest and exercise radionuclide angiography over several years, we retrospectively identified 34 patients with left main coronary artery disease and 103 patients with three-vessel coronary artery disease who did not have significant left main disease. The results of gated equilibrium radionuclide angiography were compared in these 2 groups. Multiple exercise hemodynamic, exercise electrocardiographic, and exercise radionuclide angiographic parameters were considered in an attempt to separate the 2 groups. The only parameter that was significantly different between the 2 groups was exercise heart rate. However, no value of the exercise heart rate could meaningfully separate the 2 groups. Despite their known difference in prognosis, patients with left main and three-vessel disease had very similar exercise performance and could not be distinguished from one another by exercise electrocardiography or exercise radionuclide angiography. The inability to distinguish these two groups is a clear limitation of noninvasive exercise modalities.