This study examines the relation between myocardial ischemia and the left ventricular (LV) ejection fraction (EF) response to exercise in patients with normal or abnormal resting EF. We studied 69 patients aged 25 to 78 years (mean 52 years) by radionuclide ventriculography (at rest and during peak upright exercise) and by exercise thallium-201 imaging. In 27 patients with resting EF <50%, the EF response to exercise was normal (≥5% increase) in 13 patients and abnormal in 14. The thallium scans showed reversible defects in 11 of the 14 patients (79%) with abnormal response but none in any of the patients with normal responses (p = 0.0001). In the 42 patients with resting EF ≥50%, the EF response to exercise was normal in 23 and abnormal in 19. Reversible defects were present in 13 of the 19 patients (68%) with abnormal response and in only 3 of 23 patients (13%) with normal response (p = 0.0001). Therefore, an abnormal EF response to exercise was seen in 11 of 11 patients with resting EF <50% and in 13 of 16 patients (81%) with resting EF ≥50% who had reversible thallium defects; normal EF responses were seen in 13 of the 16 patients (81%) with resting EF <50% and in 20 of 26 patients (77%) with resting EF ≥50% who had no reversible thallium defects. Thus, in patients with abnormal resting LV function an abnormal EF response to exercise suggests the presence of myocardial ischemia rather than a nonspecific response to stress. © 1985.