BACKGROUND: A major cause of the limited longevity of total ankle replacements is premature polyethylene component wear, which can be induced by high joint contact pressures. We implemented a computational model to parametrically explore the hypothesis that intercomponent positioning deviating from the manufacturer's recommendations can result in pressure distributions that may predispose to wear of the polyethylene insert. We also investigated the hypothesis that a modern mobile-bearing design may be able to better compensate for imposed misalignments compared with an early two-component design. METHODS: Two finite element models of total ankle replacement prostheses were built to quantify peak and average contact pressures on the polyethylene insert surfaces. Models were validated by biomechanical testing of the two implant designs with use of pressure-sensitive film. The validated models were configured to replicate three potential misalignments with the most CLINICAL RELEVANCE: version of the tibial component, version of the talar component, and relative component rotation of the two-component design. The misalignments were simulated with use of the computer model with physiologically relevant boundary loads. RESULTS: With use of the manufacturer's guidelines for positioning of the two-component design, the predicted average joint contact pressures exceeded the yield stress of polyethylene (18 to 20 MPa). Pressure magnitudes increased as implant alignment was systematically deviated from this reference position. The three-component design showed lower-magnitude contact pressures in the standard position (<10 MPa) and was generally less sensitive to misalignment. Both implant systems were sensitive to version misalignment. CONCLUSIONS: In the tested implants, a highly congruent mobile-bearing total ankle replacement design yields more evenly distributed and lower-magnitude joint contact pressures than a less congruent design. Although the mobile-bearing implant reduced susceptibility to aberrant joint contact characteristics that were induced by misalignment, predicted average contact stresses reached the yield stress of polyethylene for imposed version misalignments of >5 degrees.