Objectives: The aim of this study was to assess the performance of β-methyl-p-[123I]-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) to detect acute coronary syndromes (ACS) in emergency department patients with chest pain. Background: Emergency department diagnosis of chest pain is problematic, often requiring prolonged observation and stress testing. BMIPP SPECT detects abnormalities in fatty acid metabolism resulting from myocardial ischemia, even many hours after symptom cessation. Methods: Emergency department patients with suspected ACS were enrolled at 50 centers. Patients received 5 mCi BMIPP within 30 h of symptom cessation. BMIPP SPECT images were interpreted semiquantitatively by 3 blinded readers. Initial clinical diagnosis was based on symptoms, initial electrocardiograms, and troponin, whereas the final diagnosis was based on all available data (including angiography and stress SPECT) but not BMIPP SPECT. Final diagnoses were adjudicated by a blinded committee as ACS, intermediate likelihood of ACS, or negative for ACS. Results: A total of 507 patients were studied and efficacy was evaluated in 448 patients with sufficient data. The sensitivity of BMIPP by 3 blinded readers for a final diagnosis of ACS and intermediate likelihood of ACS was 71% (95% confidence interval [CI]: 64% to 79%), 74% (95% CI: 68% to 81%), and 69% (95% CI: 62% to 77%); the corresponding specificity of BMIPP was 67% (95% CI: 61% to 73%), 54% (95% CI: 48% to 60%), and 70% (95% CI: 64% to 76%). Compared with the initial diagnosis alone, BMIPP + initial diagnosis increased sensitivity from 43% to 81% (p < 0.001), negative predictive value from 62% to 83% (p < 0.001), and positive predictive value from 41% to 58% (p < 0.001), whereas specificity was unchanged (61% to 62%, p = NS). Conclusions: The addition of BMIPP data to the initially available clinical information adds incremental value toward the early diagnosis of an ACS, potentially allowing determination of the presence or absence of ACS to be made earlier in the evaluation process. (Safety and Efficacy Iodofiltic Acid I 123 in the Treatment of Acute Coronary Syndrome [Zeus-ACS]; NCT00514501). © 2010 American College of Cardiology Foundation.