Due to the complexity of the human musculoskeletal system and intra/intersubjects variability, powered exoskeletons are prone to human–robot misalignments. These induce undesired interaction forces that may jeopardize safe operation. Uncompensated inertia of the robotic links also generates spurious interaction forces. Current design approaches to compensate for misalignments rely on the use of auxiliary passive degrees of freedom that unavoidably increase robot inertia, which potentially affects their effectiveness in reducing undesired interaction forces. Assessing the relative impact of misalignment and robot inertia on the wearer can, therefore, provide useful insights on how to improve the effectiveness of such approaches, especially in those situations where the dynamics of the movement are quasi-periodic and, therefore, predictable such as in gait. In this paper, we studied the effects of knee joint misalignments on the wearer's gait, by using a treadmill-based exoskeleton developed by our group, the ALEX II. Knee joint misalignments were purposely introduced by adjusting the mismatch between the length of the robot thigh and that of the human thigh. The amount of robot inertia reflected to the user was adjusted through control. Results evidenced that knee misalignment significantly changes human–robot interaction forces, especially at the thigh interface, and this effect can be attenuated by actively compensating for robot inertia. Misalignments caused by an excessively long robot thigh are less critical than misalignments of equal magnitude deriving from an excessively short robot thigh.