A prospective, multicenter trial was conducted in patients with nontraumatic chest pain in 4 hospitals to determine whether an 80-lead body surface map electrocardiogram system (80-lead BSM ECG) improves detection of ST-segment elevation in acute myocardial infarction (STEMI) compared with a standard 12-lead electrocardiogram (ECG) in an emergency department (ED) setting. A trained ED or cardiology staff member (technician or nurse) recorded a 12-lead ECG and 80-lead BSM ECG from each subject at initial presentation. Serial biomarkers (total creatine kinase [CK], CK-MB, and/or troponin) were obtained according to individual hospital practice. Of the 647 patients evaluated, 589 had available biomarkers results. Eighty-lead BSM ECG improved detection of biomarker-confirmed STEMI compared with the 12-lead ECG for CK-MB–defined STEMI (100% vs 72.7%, P = .031; n = 364) or troponin-defined STEMI (92.9% vs 60.7%, P = .022; n = 225). Specificity for STEMI was high (range, 94.9%-97.1%) with no significant difference between 80-lead BSM ECG and 12-lead ECG. Right ventricular involvement complicating inferior STEMI was detected by 80-lead BSM ECG in 2 (22%) of 9 patients with CK-MB–defined MI and in 2 (22%) of 9 patients with troponin-defined MI. The infarct location missed most commonly on 12-lead ECG but detected by 80-lead BSM ECG was inferoposterior MI. We conclude that BSM using 80-lead BSM ECG is more sensitive for detection of STEMI than 12-lead ECG, while retaining similar specificity.