Misaligning the mechanical axes of Ankle-Foot Orthoses with the ankle axis may lead to tissue damage, reduced gait efficiency, and mechanical wear on the orthosis. Previous models developed to describe the consequences of joint misalignments have only been applied to the sagittal plane. In this study, a previously developed three-dimensional model of the Ankle-Foot Orthosis/leg system was used to determine the effects of misalignments in the frontal and transverse planes and how they interact with misalignments in the sagittal plane. The motion of two corresponding points on the leg and Ankle-Foot Orthosis was calculated for different binary combinations of translational and rotational misalignments of the mechanical axis, and the resulting displacements between those points recorded. Misaligning the mechanical joint axis of the Ankle-Foot Orthosis in the transverse plane led to much greater displacements than other misalignments. Results from the model suggest the importance of prioritizing transverse plane alignment by appropriately accounting for tibial rotation. Misalignments in the transverse plane had a dominating effect on relative motion between the Ankle-Foot Orthosis and leg emphasizing the importance of including the third dimension in the model and prioritizing accuracy of alignment in the transverse plane.