This report describes a theoretical technique which calculates the “optimal” direction and location of a fixed axis of rotation for the human knee joint. The optimization criterion is as follows; global locations of arbitrary points on the femur as a result of flexion about the fixed axis should approximate as close as possible their positions due to an equivalent anatomical motion. For comparison, an expression for the location and direction of a screw axis describing the same anatomical movement is derived. The techniques were tested by their application to blocks of known geometry. The optimal axis for two different constraint criteria and the screw axis are located in the knee of a human subject for the range of motion of complete extension to approximately 90-deg flexion. The results for the axes are compared with each other and with a commonly utilized internal prosthetic axis on the basis of ligament length patterns obtained by flexion about the different axes.