In this study, we performed structural and fatigue analyses of the engine exhaust manifold that was subjected to thermo-mechanical cyclic loading. The methodologies used in this study are based on an approach in which the techniques for modeling the exhaust system, the temperature-dependent properties of the material, and thermal cyclic loading are taken into consideration and a reliable strategy is adopted for failure prediction. An application example shows that at an elevated temperature, considerable compressive plastic deformation is observed and that at a low temperature, tensile stresses remain in those parts of the test exhaust manifold where failure is observed. In order to predict fatigue life, mechanical damage is determined on the basis of the stress.strain hysteresis loops by using the classical Coffin.Manson equation and by adopting a method in which the dissipated plastic energy is taken into consideration.