The design optimization of vehicle body structure is addressed to reduce interior noise and improve customer satisfaction in this paper. The structural-acoustic model is established and the response of sound pressure in frequency domain is obtained by using finite element method. The minimization of sound pressure near the driver's right ear depends on the geometry of vehicle body structure and the layout of damping treatments. The panel participation analysis is performed to find out the key panels as design variables and improve the efficiency of optimization computation. Response Surface Method (RSM) is utilized to optimize the vibro-acoustic properties of vehicle body structure instead of complex structural-acoustic coupling finite element model. Geometric optimization problem of panels is described and solved to minimize the interior noise in vehicle. In the optimization model, the first mode frequency, the bending and twisting stiffness of body as well as the weight are considered as constraints. The sensitivity of the objective function to design variable is calculated and the proposed optimization model is solved by using penalty function method. A set of optimal thicknesses for panels is thus obtained. The results indicate that the accuracy of the proposed RSM is sufficient to obtain a reliable optimization result. Furthermore, the proposed geometric optimization for panels can reduce interior noise in vehicle significantly and the highest sound pressure at the driver's right ear is attenuated 13 dB when the optimal thickness for panels is applied. It supplies an effective design tool to improve the quality of interior noise in vehicle.