Hemiarthroplasty is an attractive alternative to total joint replacement for the young active patient, when only one side of the synovial joint is damaged. In the development of a hemiarthroplasty prosthesis, a comprehensive understanding of the tribology of both the natural joint and the hemireplaced joint is necessary. The objectives of this study were to investigate the tribological response of polyurethane (PU) as a potential hemiarthroplasty material. Bovine medial compartmental knees were tested in a Prosim pendulum friction simulator, which applied physiologically relevant loading and motion. The healthy medial compartment was investigated as a negative control; a stainless steel hemiarthroplasty was investigated as a positive control; and three PU hemiarthroplasty plates of different moduli (1.4 MPa, 6.5 MPa, and 22 MPa) were also investigated. Using the lower-modulus PU caused reduced levels of contact stress and friction shear stress, which resulted in reduced levels of opposing cartilage wear. The two PU bearings with the lowest moduli demonstrated a similar tribological performance to the negative control. The higher-modulus PU (22 MPa) did demonstrate higher levels of friction shear stress, and wear resulted on the opposing cartilage, although not as severe as the wear from the stainless steel group. This study supports the use of compliant PU designs in future tribological experiments and hemiarthroplasty design applications.