Aims Coronary vasodilation and coronary steal are the basis for routine use of dipyridamole in stress echocardiography for non-invasive assessment of coronary artery disease (CAD). This study investigates dipyridamole effects on cardiac (regional function, synchronicity and contractility) and systemic (ventricular arterial coupling) haemodynamics during real-time three-dimensional (RT3D) stress echocardiography in very low CAD risk patients. Methods From our RT3D stress echocardiography database, we identified 132 subjects (75 men, aged 68 +/- 10 years) referred to stress echocardiography because of risk factors and/or atypical chest pain, who had normal baseline echocardiography, negative dipyridamole stress echocardiography and uneventful 2-year follow-up. All participants had good-quality RT3D datasets acquired during dipyridamole stress echocardiography (0.84 mg/kg in 10 min). From full volume datasets, ventricular volumes, regional subvolume curves and dyssynchrony index (SDI) were obtained; ventricular arterial coupling was calculated as stroke volume/end-systolic volume. Results In all participants, ventricular arterial coupling increased, whereas SDI decreased. End-systolic volume decreased and stroke index increased independently of pressure drop; the relationship between heart rate and arterial pressure changes was non-linear (quadratic regression, r = 0.368, P<0.0001). The decrease in systemic resistance showed a curvilinear behaviour with respect to the ventricular arterial coupling increase. Conclusion In a large population of normal individuals, dipyridamole administration improved ventricular energetics and better synchronization of regional contraction may be one of the mechanisms. The relationship between blood pressure and heart rate response suggests that heart rate response is of little help in identifying the systemic haemodynamic response to dipyridamole.