It shows that determination of damping matrix in the dynamic time-history analysis method strongly affects the seismic response of complex engineering structures, and the safety related structures of nuclear power plant in dynamic analysis usually adopts the dynamic time-history analysis method. To study the effect of determination of damping matrix on the seismic response of nuclear power plant structure, we consider the proportional damping fitting accuracy of nuclear power plant structure, and the influence of different shape of structure based on structural damping, to set up a more precise model, an equivalent proportional damping model. Furthermore, a corresponding method of the seismic response analysis of the nuclear power plant structure is proposed by taking consideration of structural vibration characteristics, which is, determining the proportional damping coefficient by weighted least square fitting method. The application and analysis show that the method is more consistent with the exact solution than the method with traditional damping coefficient, and it is suitable for the seismic response of nuclear power plant structure.