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A modeling approach is used in this paper to study the effects of fatigue on the ground reaction force (GRF) and the vibrations of the lower extremity soft tissues. A recently developed multiple degrees-of-freedom mass-spring-damper model of the human body during running is used for this purpose. The model is capable of taking the muscle activity into account by using a nonlinear controller that tunes the mechanical properties of the soft-tissue package based on two physiological hypotheses, namely, “constant force” and “constant vibration.” In this study, muscle fatigue is implemented in the model as the gradual reduction of the ability of the controller to tune the mechanical properties of the lower body soft-tissue package. Simulations are carried out for various types of footwear in both pre- and post fatigue conditions. The simulation results show that the vibration amplitude of the lower body soft-tissue package may considerably increase (up to 20%) with muscle fatigue, while the effects of fatigue on the GRF are negligible. The results of this modeling study are in line with the experimental studies that found muscle fatigue does not significantly change the GRF peaks, but may increase the level of soft-tissue vibrations (particularly for hard shoes). A major contribution of the current study is the formulation of a hypothesis about how the central nervous system tunes the muscle properties after fatigue.