© 2015 The American Association for Thoracic Surgery. Objective The objective of this study was to evaluate left ventricular free wall and interventricular septal function by 2-dimensional transthoracic echocardiography and live/real-time 3-dimensional transthoracic speckle tracking echocardiography before and after on-pump cardiac surgery and to assess the effect of mode of cardioplegia delivery. Methods A total of 22 patients were studied 1 day before and 4 to 5 days after surgery. Cold blood cardioplegia was delivered by intermittent antegrade infusion or by the integrated method. The latter includes a combination of intermittent antegrade and retrograde cardioplegia with a terminal warm amino acid-enriched reperfusion. Results The overall group displayed significant deterioration of septal function after surgery by 2-dimensional transthoracic echocardiography, as assessed by wall motion score index, yet subgroup analysis by 3-dimensional transthoracic speckle tracking echocardiography permitted distinction of outcomes achieved by antegrade or integrated delivery methods. Analysis after surgery showed that only the antegrade group displayed statistically significant deterioration in the strain parameters of some of the segments of the septum and free wall when strain was measured in the free wall and septum in the longitudinal, circumferential, and radial modes of deformation (P <.05). In contrast, only the integrated group displayed significant improvement in global radial, circumferential, and longitudinal strain (P <.05). Conclusions These findings by 3-dimensional transthoracic speckle tracking echocardiography indicate that integrated cardioplegia offers superior myocardial protection of the left ventricular free wall and septum compared with the antegrade mode of cardioplegia delivery.