We have performed three-dimensional high-resolution numerical simulations of a bi-leaflet mechanical heart valve implanted at different orientations in an anatomic left ventricle-aorta obtained from magnetic resonance imaging of a volunteer. The thoroughly validated overset curvilinear-immersed boundary fluid–structure interaction flow solver is used in which the aorta and left ventricle (LV) are discretized with boundary-conforming and nonconforming curvilinear grids, respectively. The motion of the left ventricle wall is prescribed based on a lumped parameter model while the motion of the leaflets is calculated using a strongly coupled fluid–structure interaction algorithm enhanced with Aitken convergence technique. We carried out simulations for three valve orientations, which differ from each other by 45 deg, and compared the leaflet motion and flow field for multiple cycles. Our results show reproducible and relatively symmetrical opening for all valve orientations. The presence of small-scale vortical structures after peak systole causes significant cycle-to-cycle variations in valve kinematics during the closing phase for all valve orientations. Furthermore, our results show that valve orientation does not have a significant effect on the distribution of viscous shear stress in the ascending aorta. Additionally, two different mathematical activation models including linear level of activation and Soares model are used to quantify the platelet activation in the ascending aorta. The results show that the valve orientation does not significantly affect (less than 8%) the total platelet activation in the ascending aorta.