We implanted an electronic knee prosthesis to measure tibial forces in vivo during activities of daily living after total knee arthroplasty. We used tibial forces and knee kinematic data collected in vivo to calculate contact stresses using finite element analysis. The polyethylene insert was modeled as an elastoplastic material, and predicted contact stresses were validated using pressure sensitive sensors. Peak contact stresses generated during walking were similar but about 18% lower than those calculated for International Standards Organization (ISO)-recommended wear simulation conditions. Stair climbing generated higher contact stresses (32 MPa) than walking (26 MPa). However, both high flexion activities (lunge and kneel) generated even higher contact stresses, with the lunge activity generating the highest stresses (56 MPa). The activities that generated high contact stresses also resulted in high equivalent plastic strain. However, the lunge activity generated dramatically higher plastic equivalent strain than the other activities. In vivo measurement of kinematics, forces, and contact stresses may be used to develop more clinically relevant wear simulator protocols. Contact stresses generated during high flexion activities were substantially higher and were largely due to the reduced contact area in deep flexion rather than due to an increase in contact forces. Our results support the use of “high flexion” designs that improve contact conditions and preserve contact area at high flexion angles.