Smart knee replacement technology seeks to provide an in vivo method of tracking long-term postoperative joint loads with the goal of identifying clinically relevant phenomena linked to postoperative dissatisfaction in real time. This study evaluated the ability of a piezoelectric compartmental force and compartmental center of pressure sensing total knee replacement to sense condylar lift-off, which is a clinically relevant phenomenon commonly attributed to postoperative dissatisfaction. A commercially available total knee replacement was modified to include six piezoelectric transducers capable of measuring compartmental forces and tibiofemoral centers of pressure on the articular surface of the tibial bearing insert. The smart knee replacement was evaluated with a six-degree-of-freedom joint motion simulator applying a varus lift-off profile. The study demonstrated that the lift-off was evident in both the sensed joint loads and the localized tibiofemoral centers of pressure obtained from the piezoelectric sensing system. The results indicated that the piezoelectric smart knee replacement could be effective for detecting this clinically problematic mechanical issue.