Myocardial deformation parameters are sensitive markers of global left ventricular (LV) systolic function, but their interaction with LV geometry is unknown. We sought to investigate the effect of LV geometry on myocardial deformation and its interaction with coronary artery disease (CAD). A total of 126 patients with normal resting LV function who underwent dobutamine stress echocardiography subsequently underwent coronary angiography within 6 months. Longitudinal myocardial deformation was calculated using tissue Doppler echocardiography. The extent of CAD was identified by quantitative coronary angiography. Patients with an increased relative wall thickness had a significantly lower peak strain rate (SR) and a smaller change in SR with stress, with no differences in the at rest values. Those with CAD, had significantly lower peak SR values and change in SR with no difference in resting measures. A linear regression model showed that the relative wall thickness and extent of CAD were the strongest predictors of change in SR. An increasing extent of CAD caused a steady degradation in the peak SR and change in peak SR. Markers of longitudinal myocardial deformation at peak stress reflect both myocardial and interstitial properties. In conclusion, a major determinant of subendocardial function is the wall thickness, as measured by the relative wall thickness, and not LV hypertrophy.