In recent years, for the sake of energy saving and environment protection, lightweight body structure becomes the trend of vehicle development. Based on this objective, it is significant to make a research on optimization for the body structure. When structure optimization for the single work condition is carried out, the common mechanism optimization design method can provide the optimum result for certain condition according to the corresponding restriction and objective functions, whereas, the same variable has different variation trends in different conditions. In order to satisfy the requirements of the actual condition with multi-load cases optimization, synthesis analysis should be carried out by introducing weights for corresponding variables. First of all, the optimization section sizes of frame members of one semi-integral fuel cell bus body are analyzed respectively under four different load cases by applying common mechanism optimization design method. Furthermore, orthogonal design of experiment method is adopted to analyze the effect factor of the four optimization results in the synthesis optimization analysis and ascertain the integral optimum scheme. By analyzing and checking the bus body gained from the optimum synthesis scheme, it is confirmed that the synthesis optimization method for structure by adopting both common mechanism optimization design method and orthogonal design of experiment method can be used to carry out the optimization analysis under multi-load cases for bus body frame and the lightweight of bus framework, on the premise of ensuring the bus body performance index such as strength, stiffness and mode.