Abstract Purpose To assess stress-echo (SE) diagnostic performance in patients presenting to the emergency department (ED) with spontaneous chest pain, especially in subgroups in which exercise ECG diagnostic performance has been questioned (women, elderly, history of coronary artery disease). Methods Between June 2008 and May 2011, 474 patients with an episode of spontaneous chest pain, non-diagnostic electrocardiogram and negative cardiac necrosis markers underwent SE. Patients with inducible ischemia (Isch) were asked to undergo coronary angiography. Patients with negative SE were discharged and contacted by telephone at least 6 months after discharge, to ascertain the occurrence of new cardiac events. Main findings Exercise stress-echo (ESE) was employed in 270 patients and dobutamine (DSE) in 218 (including 14 with inconclusive ESE); a diagnosis of coronary artery disease (CAD) was confirmed or excluded in 434 (92%) patients. SE was negative for Isch in 318 patients (206 ESE and 112 DSE) and positive in 132. During follow-up, patients with negative SE had 4 cardiac events. SE showed: sensitivity 90%, specificity 92%, positive predictive value 78% and negative predictive value 97%. Sensitivity was comparable between patients aged < or ≥ 70 years (84 vs 94%) and between gender (89 vs 96%), but lower in patients with known CAD (88 vs 94%, P < .05); specificity was comparable regardless of age (94 vs 99%) and presence of CAD (97 vs 91%), but was lower among women (87 vs 96%, P < .05). Conclusions SE had a very good diagnostic performance in ED patients with suspected Isch, both overall and in selected high-risk groups.