Ventricular assist devices (VADs) became in recent years the standard of care therapy for advanced heart failure with hemodynamic compromise. With the steadily growing population of device recipients, various postimplant complications have been reported, mostly associated with the hypershear generated by VADs that enhance their thrombogenicity by activating platelets. Although VAD design optimization can significantly improve its thromboresistance, the implanted VAD need to be evaluated as part of a system. Several clinical studies indicated that variability in implantation configurations may contribute to the overall system thrombogenicity. Numerical simulations were conducted in the HeartAssist 5 (HA5) and HeartMate II (HMII) VADs in the following implantation configurations: 1) inflow cannula angles: 115° and 140° (HA5); 2) three VAD circumferential orientations: 0°, 30°, and 60° (HA5 and HMII); and 3) 60° and 90° outflow graft anastomotic angles with respect to the ascending aorta (HA5). The stress accumulation of the platelets was calculated along flow trajectories and collapsed into a probability density function, representing the “thrombogenic footprint” of each configuration—a proxy to its thrombogenic potential (TP). The 140° HA5 cannula generated lower TP independent of the circumferential orientation of the VAD. Sixty-degree orientation generated the lowest TP for the HA5 versus 0° for the HMII. An anastomotic angle of 60° resulted in lower TP for HA5. These results demonstrate that optimizing the implantation configuration reduces the overall system TP. Thromboresistance can be enhanced by combining VAD design optimization with the surgical implantation configurations for achieving better clinical outcomes of implanted VADs.