An alternative approach to extract 3D myocardial strain based on elastic registration of the ultrasound images (3DSE) was developed by our lab. The aim of the present study was to test its clinical performance by comparing strain values obtained by 3DSE with the ones obtained with 2D speckle tracking (2DST). Standard 2D B-mode and volumetric datasets were acquired in 12 patients with coronary heart disease (CHD) and in 12 control subjects. Longitudinal (ε(LL)), circumferential (ε(CC)) and radial (ε(RR)) strain values were obtained from 2D datasets using commercially available 2DST software and from volumetric datasets using the 3DSE approach. 3DSE provided lower strain values than 2DST. With both approaches global ε(LL) and ε(CC) were significantly lower in patients with CHD than in controls. Global ε(LL) and ε(CC) correlated well between both methods (R = 0.83, R = 0.86, respectively), while segmental correlations were moderate [R = 0.63 (ε(LL)), R = 0.41 (ε(CC))]. The highest differences in ε(LL) values obtained by the two methods and the highest number of erroneous ε(LL) with 3DSE were observed in the basal LV segments. This study shows that in real-life datasets our 3DSE method provides global and regional ε(LL) and ε(CC) values that are comparable with the ones obtained from 2DST, even though they are not interchangeable with each other. As only a single acquisition is required, 3D methods may offer advantages over the current 2D techniques. However, the accuracy of the 3DSE can still be improved by solving the problems that appear with deformation estimation in the basal segments.