OBJECTIVE We sought to evaluate the clinical use and cost-analysis of acute rest technetium-99m (Tc-99m) tetrofosmin single-photon emission computed tomographic (SPECT) myocardial perfusion imaging in patients with chest pain and a normal electrocardiogram (ECG). BACKGROUND Current approaches used in emergency departments (EDs) for treating patients presenting with chest pain and a nondiagnostic ECG result in poor resource utilization. METHODS Three hundred fifty-seven patients presenting to six centers with symptoms suggestive of myocardial ischemia and a nondiagnostic ECG underwent Tc-99m tetrofosmin SPECT during or within 6 h of symptoms. Follow-up evaluation was performed during the hospital period and 30 days after discharge. All entry ECGs, SPECT images and cardiac events were reviewed in blinded manner and were not available to the admitting physicians. RESULTS By consensus interpretation, 204 images (57%) were normal, and 153 were abnormal (43%). Of 20 patients (6%) with an acute myocardial infarction (MI) during the hospital period, 18 had abnormal images (sensitivity 90%), whereas only 2 had normal images (negative predictive value 99%). Multiple logistic regression analysis demonstrated abnormal SPECT imaging to be the best predictor of MI and significantly better than clinical data. Using a normal SPECT image as a criterion not to admit patients would result in a 57% reduction in hospital admissions, with a mean cost savings per patient of $4,258. CONCLUSIONS Abnormal rest Tc-99m tetrofosmin SPECT imaging accurately predicts acute MI in patients with symptoms and a nondiagnostic ECG, whereas a normal study is associated with a very low cardiac event rate. The use of acute rest SPECT imaging in the ED can substantially and safely reduce the number of unnecessary hospital admissions.