Background: Stress echocardiography (SE) is an established technique for assessment of coronary artery disease (CAD) which is difficult to perform and interpret. Left ventricular stroke volume (SV) is readily estimated with Doppler echocardiography. It can be affected by myocardial ischemia, with possible adjunctive value during SE. Methods: Patients underwent Bruce protocol SE with SV estimated before and after maximal treadmill exertion post routine regional wall analysis. Incremental change in SV (ΔSV) with exercise was measured. Results: A derivation cohort (n=273) was established to test the hypothesis. An optimal cut-off for detection on inducible ischemia was ΔSV ≤ +10ml. The validation cohort of consecutive patients (n = 1093, 376 [34%] female; age 59±12 years) were followed clinically after SE for 20,460 patient-months. There were 1000 patients with non-ischemic SE, and 93 patients with studies suggestive of myocardial ischemia. Secondary analysis yielded 831 patients with a normal exercise response (ΔSV > +10ml) and 192 with an abnormal ΔSV ≤ +10ml. Time to first combined adverse cardiac event (composite of angina, acute coronary syndrome, cardiac revascularization, worsening New York Heart Association (NYHA) class, a reduction in EF, and cardiovascular death) was analysed and adjusted using Cox proportional hazards regression. The hazard ratio for an adverse event with an abnormal ΔSV response (≤10ml) was 10.3 (95% confidence intervals 5.6-19.1, p<0.0001). Conclusions: SV assessment during SE is feasible and readily performed. It is simple, practical and has incremental diagnostic and prognostic value when added to exercise regional wall motion analysis.