In the Agility® total ankle replacement system, motion is constrained by the implant’s articulating surfaces and the peri-ankle ligaments. The effects of plausibly occurring implant malpositioning on peri-ankle ligament functional extension during walking were explored in this study. The intent was to determine whether certain ligaments could serve as guides to assist in proper component positioning at implantation. Using a cadaver preparation with simulated physiologic motion and loading, we monitored change of ligament length of the anterior talofibular, posterior talofibular, calcaneofibular, and tibiocalcaneal ligaments resulting from controlled malpositioning of the tibial component relative to a neutral position. During a simulated walking cycle, effects of mediolateral and anterior/posterior translation, internal and external rotation, inversion and eversion, and elevation of the component were evaluated. In all cases, tibial component displacement from the neutral position caused atypical length change in one or more of the peri-ankle ligaments. In particular, anterior/posterior displacement significantly changed the lengthening behavior of all four tested ligaments. The anterior talofibular ligament was sensitive to transverse plane displacements, whereas the tibiocalcaneal ligament was sensitive to coronal plane displacements. For the Agility® prosthesis, these two ligaments seem to be sensitive guides for tibial component positioning at implantation.