Being a semicrystalline polymer, polytetrafluoroethylene (PTFE) has been used in sophisticated applications as biological implants where mechanical properties like low coefficient of friction, resistance to corrosion, and biocompatibility are the major concerns. However, these substitutes should own longevity for continuous working against cyclic loading conditions. In this study, friction effect on the fatigue life of PTFE has been observed through experimental and numerical analysis. Asymptotic behavior of penetration depth relation with fatigue life suggests consideration on friction fatigue. Conditional load application on rotating specimen showed that, while being used as substrate under cyclic loading, shape optimization should be considered as design factor.