Abstract: An optimum design method of gantry machining center cross beam was introduced from the initial configuration design to the final determination of the reinforcement bar specific size. The mathematical model of topology optimization based on variable density method was first established in which the moving load was considered. The iterative formula was deduced with optimality criteria method and a filtering function with volume constraint was imported to solve the problem of checkerboard and mesh independence. After the preparation of MATLAB program, the initial configuration of the beam was obtained. Then, the response surface model was established to calculate the sensitivity of stiffness and natural frequency to the thickness of the main plate. NSGA-Ⅱ with elitist strategy was used to optimize the response surface model, and after selection of the optimal solution in Pareto solution set, rounding correction of the design variables based on sensitivity analysis was implemented. By comparing with the original design data, the reliability and feasibility of the method in this paper were proved, which provides theoretical guidance for the optimization design of cross beam of gantry machining center, and also provides reference for the optimization design of other similar structures.