A computational method of fluid-structure coupling is implemented to predict the fatigue response of a high-pressure turbine blade. Two coupling levels, herein referred to as a “fully coupled” and “decoupled” methods are implemented to investigate the influence of multi-physics interaction on the 3 D stress state and fatigue response of a turbine blade. In the fully-coupled approach, the solutions of the fluid-flow and the solid-domain finite element problem are obtained concurrently, while in the decoupled approach, the independently computed aerodynamic forces are unilaterally transferred as boundary conditions in the subsequent finite element solution. In both cases, a three-dimensional unsteady stator-rotor aerodynamic configuration is modelled to depict a forced-vibration loading of high-cycle failure mode. Also analyzed is the low-cycle phenomenon which arises due to the mean stresses of the rotational load of the rotating turbine wheel. The coupling between the fluid and solid domains (fully-coupled approach) provides a form of damping which reduces the amplitude of fluctuation of the stress history, as opposed to the decoupled case with a resultant higher amplitude stress fluctuation. While the stress amplitude is higher in the decoupled case, the fatigue life-limiting condition is found to be significantly influenced by the higher mean stresses in the fully-coupled method. The differences between the two approaches are further explained considering three key fatigue parameters; mean stress, multiaxiality stress state and the stress ratio factors. The study shows that the influence of the coupling between the fluid and structures domain is an important factor in estimating the fatigue stress history.