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This paper presents a fatigue damage model to estimate fatigue lives of microelectromechanical systems (MEMS) devices and account for the effects of topological randomness of material microstructure. For this purpose, the damage mechanics modeling approach is incorporated into a new Voronoi finite-element model (VFEM). The VFEM developed for this investigation is able to consider both intergranular crack initiation (debonding) and propagation stages. The model relates the fatigue life to a damage parameter "D" which is a measure of the gradual material degradation under cyclic loading. The fatigue damage model is then used to investigate the effects of microstructure randomness on the fatigue of MEMS. In this paper, three different types of randomness are considered: (1) randomness in the microstructure due to random shapes and sizes of the material grains; (2) the randomness in the material properties considering a normally (Gaussian) distributed elastic modulus; and (3) the randomness in the material properties considering a normally distributed resistance stress, which is the experimentally determined material property controlling the ability of a material to resist the damage accumulation. Thirty-one numerical models of MEMS specimens are considered under cyclic axial and bending loading conditions. It is observed that the stress-life results obtained are in good agreement with the experimental study. The effects of material inhomogeneity and internal voids are numerically investigated.