The ground motions of foundations in mountainous regions vary at different elevation, and the degree of impacts on the seismic response of buildings in the areaneeds to be studied. By forming the Wenchuan earthquake records from Zigong observation array as the inputs, four RC (reinforced concrete) frame structures supported by stepped foundations were designed based on Chinese National Standard for seismic design of buildings. The elastic and elastoplastic time history analysis of the structure of the calculation example was carried out by inputting the ground motion signal at upper surface of the foundation, at lower surface or the multiple points at both surfaces. Structural seismic response difference coefficient is defined as the ratio of the response to the single excitation signal at one surface over the response to the multi-point excitation inputs at both surfaces. The influence of multipoint input on the seismic response of the spatial RC frame structures supported by stepped foundationsis analyzed in the aspects of structural seismic response difference coefficients and failure modes. The results are following:In the elastic analysis, the difference coefficient of seismic response of lateral deformation and storey shear of RC frame structure with long 1stnatural period is between 0.85 and 1.12, while the value is between 0.38 and 1.22 for similar structures with relatively shorter 1st natural period. Thus, the RC frame structures supported by stepped foundationsdesigned only based on the single ground motion signal on one surface may be unsafe. In the elastoplastic analysis, the seismic response of the RC frame structures supported by stepped foundations with both long and short periods under multi-input is obviously different from that under uniform input, and the minimum difference coefficient can reach 0.27; The failure state of the bottom of the RC frame structure under multi-point input is more severe than that under single inputunder the extremely rare earthquake. Proper seismic strengthening should be carried out for the step part and the first floor above the sill of the RC frame structures supported by stepped foundations.