Preclinical endurance testing of total knee replacements (TKRs) is performed using International Organization for Standardization (ISO) load and motion protocols. The standards are based on data from normal subjects and may not sufficiently mimic in vivo implant conditions. In this study, a mathematical model was used to calculate the axial force profile of 30 TKR patients with two current implant types, 22 with NexGen and eight with Miller-Galante II Cruciate-Retaining TKRs, and statistically compare the axial force specified by the ISO standard to the TKR patients. Significant differences were found between the axial forces of both groups of TKR patients and the ISO standard at local maxima and minima points in the first half of stance. The force impulse (area under the axial force curve, representing cumulative loading) was smaller for the ISO standard than the TKR patients, but only for those with NexGen implants. Waveform analysis using the coefficient of multiple correlation showed that the ISO and TKR patient axial force profiles were similar. The combined effect of ISO standard compressive load and motion differences from TKR patients could explain some of the differences between the wear scars on retrieved tibial components and those tested in total joint simulators.