PURPOSE: To investigate the relationship between the development of ischemia during stress testing and the changes in left ventricular ejection fraction (LVEF) measurements obtained after stress and at rest with a same-day perfusion-function imaging protocol. MATERIALS AND METHODS: One hundred twenty-six patients underwent a same-day rest-stress (61%) or stress-rest (39%) protocol and gated single photon emission computed tomography (SPECT). Perfusion analysis was performed with a 12-segment model. Defects were scored (0 = no defect, 1 = mild defect, 2 = moderate defect, and 3 = severe defect); differences between the summed stress and resting scores of greater than three indicated substantial ischemia. RESULTS: Resting and poststress LVEFs correlated significantly (r = 0.97, P <.001); however, patients with and patients without ischemia had significant differences in poststress versus resting LVEFs (-4.0 vs 1.0, respectively; P <.01). In patients with ischemia versus patients without ischemia, subgroup analysis stress-rest (-2.5 vs 1.0, P =.047) and rest-stress (-4.0 vs 1.0, P =.006) protocols yielded similar results. CONCLUSION: In patients with clinically important stress-induced perfusion abnormalities, the LVEF after stress was significantly lower than the LVEF at rest with same-day rest-stress and stress-rest imaging protocols. In the clinical setting, poststress LVEFs may be lower than true resting measurements, particularly in patients with moderate to severe stress-induced ischemia.