Left ventricular assist device (LVAD) support unloads left ventricular (LV) pressure and volume and decreases wall stress. This study investigated the effect of systematic LVAD unloading on the 3-dimensional myocardial wall stress by employing finite element models containing layered fiber structure, active contractility, and passive stiffness. The HeartMate II^® (Thoratec, Inc., Pleasanton, CA) was used for LV unloading. The model geometries and hemodynamic conditions for baseline (BL) and LVAD support (LV_support) were acquired from the Penn State mock circulatory cardiac simulator. Myocardial wall stress of BL was compared with that of LV_support at 8,000, 9,000, 10,000 RPM, providing mean pump flow (Q _mean) of 2.6, 3.2, and 3.7 l/min, respectively. LVAD support was more effective at unloading during diastole as compared to systole. Approximately 40, 50, and 60 % of end-diastolic wall stress reduction were achieved at Q _mean of 2.6, 3.2, and 3.7 l/min, respectively, as compared to only a 10 % reduction of end-systolic wall stress at Q _mean of 3.7 l/min. In addition, there was a stress concentration during systole at the apex due to the cannulation and reduced boundary motion. This modeling study can be used to further understand optimal unloading, pump control, patient management, and cannula design.