Background Epicardial potentials (EP) derived from body surface potentials using a thoracic volume conductor model (TVCM) improve acute myocardial infarction (AMI) diagnosis. In this study, we compared EP derived from the 80-lead body surface potential map (BSPM) using a TVCM developed from CT imaging with other electrocardiographic techniques in AMI diagnosis. Methods In this prospective study, consecutive patients presenting to both the ED and pre-hospital coronary care unit between August 2009 and August 2011 with acute ischaemic-type chest pain at rest were enrolled. At first medical contact a 12-lead electrocardiogram (ECG) and BSPM were recorded. Cardiac troponin-T (cTnT) was sampled 12 h after symptom onset. AMI was diagnosed when cTnT ≥0.1 µg/l. Patients were excluded from analysis if they had bundle branch block, permanent pacemaker, left ventricular hypertrophy by voltage criteria or concomitant digitalis therapy. A cardiologist assessed the 12-lead ECG for STEMI by Minnesota criteria and the BSPM. BSPM ST-elevation (STE) was ≥0.2 mV in anterior, ≥0.1 mV in lateral, inferior, right ventricular (RV) or high right anterior and ≥0.05 mV in posterior territories indicating AMI. To derive EP, the 80-lead BSPM data were interpolated (Laplacian method) to yield values at 352-nodes of a Dalhouse torso. Using an inverse solution based on the boundary element method employing Tikhonov regularisation, EP at 98 cardiac nodes positioned within a standard TVCM were estimated. EP ≥0.3 mV defined STE. A cardiologist blinded to both the 12-lead ECG and BSPM interpreted the EP map. Results Enrolled were 400 patients (age 62±13 years; 57% male): 80 patients had exclusion criteria. Of the remaining 320 patients, 180 (56%) had AMI. Of these 180 patients, 117 had STEMI by Minnesota criteria (sensitivity 65%, specificity 89%) and 146 had BSPM STE (sensitivity 81%, specificity 90%). EP STE occurred in 158 patients (sensitivity 88%, specificity 95%, p Conclusions Among those with an initial non-diagnostic 12-lead ECG, EP derived from BSPM using a TVCM significantly improves AMI diagnosis.