The load on the prosthetic side and the influence of the design on the remaining natural contralateral TMJ must be known before a unilateral temporomandibular joint (TMJ) prosthesis can be developed. The aim of the present study was to determine the maximum loading of the TMJ prosthetic side and the natural contralateral TMJ and to investigate the influence of the location of the center of rotation of the prosthesis on the maximum loading. For this purpose, a mathematical model of the mandible with a unilateral TMJ prosthesis with a fixed center of rotation (CR) was developed. The location of the CR of the TMJ prosthesis was varied from the middle of the natural mandibular condyle to 15 mm inferior to this location. Although the maximum joint reaction forces changed as a result of a unilateral TMJ prosthesis, the trend of the loading curves was similar to that of an intact mandible. A unilateral TMJ prosthesis resulted in a 50% higher loading of the prosthetic side, while the load on the natural contralateral TMJ remained within normal limits. The maximum load on the prosthetic side occurred during molar bites and could reach 100 N in the cranial direction, 30 N in the ventral direction, and 25 N in the medio-lateral direction. The location of the CR did not have a significant influence on the loading of the TMJ prosthesis and the natural contralateral TMJ.