The gearbox case is required to be lightweight under harsh service conditions and complex loads. As an important evaluation index of the case, how to ensure the misalignment of the bearing hole and realize the lightweight has become a major challenge. To address this issue, a topology optimization method for aero-engine gear transmission case, considering the mechanical-inertial load effects, is proposed based on the SIMP interpolation penalty model. The influence of inertial loads on the case attachments is incorporated into the optimization model, with constraints on case stress, dangerous bearing bore misalignment, and optimized region volume fraction. The objective is to minimize the weighted compliance of the case under different conditions, achieving a 7.1% reduction in case weight while decreasing maximum von Mises stress, deformation, and dangerous bearing bore misalignment by 7.1%, 3.1% and 11.1%, respectively.