Preclinical evaluation of the wear of total knee replacements (TKR) is usually undertaken using International Standards Organization (ISO) test methods. Two international standards for the preclinical wear simulation of TKRs have been developed; using either force or displacement control. In addition, based on previously published measured kinematics of healthy subjects, a gait cycle (displacement control) was also developed at the University of Leeds, which pre-dates the ISO displacement control standard. Furthermore, different test methods have adopted different approaches to defining the centres of rotation and polarity (direction of application) of motions. However, the effects of using these different control regimes and input conditions on the kinematics, contact mechanics, and wear of any one TKR have not been fully investigated previously.The current study investigated the kinematics, contact mechanics, and wear performance of a TKR when running under ISO force and displacement control test methods as well as the Leeds gait cycle inputs using experimental and computational simulation methods, with the aim of understanding the mechanical and tribological outcomes predicted by the different test method standard conditions. Three ISO wear testing standards were investigated using a mid-size Sigma curved TKR (DePuy, UK), with moderately cross-linked UHMWPE curved inserts; ISO-14243-3-2004, ISO-14243-3-2014 and ISO-14243-1-2009. In addition, the Leeds displacement control gait cycle was also investigated.According to the computational simulation predictions, reversing the anterior-posterior (AP) displacement and tibial rotation polarities in the displacement control ISO-2014 standard compared to the ISO-2004 standard resulted in high stress, of more than 65 MPa, at the posterior edge of the inserts with more than 10% increase in wear rate for this TKR design. Although Leeds gait input kinematics produced femoral rollback, it did not result in high stress edge loading on the posterior lip of the insert. This was attributed to different test input kinematics and different centres of rotation of the femoral component adopted in the displacement control standard ISO-2014 and Leeds gait test methods. The predicted AP displacement and tibial rotation from the force control ISO-2009 had different polarities and magnitudes to the corresponding displacement control profiles. In addition, the predicted wear rate, from the computational model, under the force control ISO-2009 standard was more than double that predicted under displacement control ISO standards due to the increased AP displacement and tibial rotation motions predicted under the force control standard.These major differences, in the mechanics and wear, between different test methods imply that each standard must therefore be used with its own predicate control results from a device with proven clinical history and results across different standards should never be compared, as the choice of test method standard may well be dependent on the design solution for the knee. Clinically, the kinematics in the population are extremely variable, which results in highly variable wear rates. While a standard method is necessary, on its own it is not adequate and needs to be supported by tests under a portfolio of representative conditions with different kinematic conditions, different soft tissue constraints, as well as with different alignments, so that the variability and range of wear rates expected clinically might be determined. This study enables further progress towards the definition of such a portfolio of representative conditions, by deepening the understanding of the relationships between currently used input conditions and the resulting mechanical and wear outputs.