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Misalignment was identified as a cause for failure of total ankle replacement (TAR) [1,2]. The presumed mechanism leading to this failure is altered mechanical properties leading to elevated and concentrated contact pressure [1] and increased in micro-motion [2]. In this study we use image-based, three-dimensional (3D) musculoskeletal models to identify the changes in ankle mechanics due to TAR misalignment. Previously developed and validated 3D musculoskeletal models of the ankle complex were used to identify the effect of TAR misalignment on joint mechanics. A generic TAR with cylindrical articular surfaces replaced the natural surfaces of the ankles. The tibial and talar components were first inserted in an optimal fashion with the surfaces parallel to each other. A misalignment was then produced by translating (2 mm Elevation/Depression, 3 mm Anterior/Posterior) and rotating (10º Dorsi/Plantar Flexion, 10º Inversion/Eversion, 10º Internal/External Rotation) the tibial component. Simulations, conducted in ADAMSTM consisted of loading the model in all three planes while recording the applied loads, the displacements produced and the forces in the ligaments. From these results the following parameters were derived: surface-to-surface distance maps at the ankle, Range of Motion (ROM), stiffness, ligament forces, ligament strains, and kinematic couplings. Misalignment of the tibial component of TAR produces changes in the stiffness of the ankle joint complex, changes in the surface to surface interaction at the ankle joint and affects the forces and strains developed in the surrounding ligaments. Knowledge of the effect of misalignment of TAR is clinically relevant since it indicates the sensitivity of the mechanical behavior of the joint to component misalignment [3]. As such, this technique can be used as a predictive tool to indicate the most sensitive direction in which misalignment is critical.