Current guidelines recommend the use of exercise stress echocardiography (ESE) in patients with unexplained dyspnoea. SE was recently reshaped with the ABCDE protocol: A for asynergy, B for B-lines (4-site simplified scan), C for contractile reserve based on force, D for Doppler-based coronary flow velocity reserve (CFVR) in left anterior descending coronary artery; and E for EKG-based heart rate reserve (HRR, defined as peak/rest HR < 1.62). Aim of the study was to define the ESE response in patients with dyspnoea as the main symptom. From the initial population of patients referred in 2018 in a single center for semi-supine ESE, we selected two groups (without history of previous myocardial infarction or coronary revascularization) on the basis of the main presenting symptom: dyspnoea (Group 1, n = 100, 62 men, 63 ± 10 years) or chest pain (Group 2, n = 100, 58 men, age 61 ± 8 years). All underwent ESE with ABCDE protocol. Success rate was 100% for steps A, B, C, E, and 88% for step D. Positivity for A criterion occurred in 56 patients of Group 1 and 24 of Group 2 (p < 0.0001). B-lines positivity (stress > rest for ≥ 2 points) occurred in 40 patients of Group 1 and 28 of Group 2 (p = 0.07). LVCR positivity (< 2.0) occurred in 60 patients of Group 1 and 42 of Group 2 (p < 0.05). A reduced CFVR occurred in 56 of Group 1 and 22 of Group 2 (p < 0.0001). A blunted HRR was present in 44 patients of Group 1 and 22 of Group 2 (p < 0.001). In conclusion, in patients with unexplained dyspnoea, SE with ABCDE protocol is useful to document the cardiac origin of dyspnoea with a comprehensive assessment focused not only on ischemia (A) but also pulmonary congestion (B), myocardial scar or necrosis (C), coronary microvascular dysfunction (D) or chronotropic incompetence (E).