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Due to the high center of gravity of medium-duty vehicles, rollover accidents can easily occur during high-speed cornering and lane changes. In order to prevent the deformation of the body structure, which would restrict the survival space and cause compression injuries to occupants, it is necessary to investigate methods for mitigating these incidents. This paper establishes a numerical model of right-side rollover for a commercial medium-duty vehicle in accordance with ECE R66 regulations, and the accuracy of the model is verified by experiment. According to the results, the material and size parameters of the key components of the right side pillar are selected as design variables. The response result matrix was constructed using the orthogonal design method for total mass, energy absorption, maximum collision acceleration, and minimum distance from the survival space.