In this study, it is aimed to determine the effects of soil-structure interaction (SSI) and multiple-support excitation on the dynamic characteristics of the seismic response of cable-stayed bridges. For this purpose, ground motion time histories are generated for multiple-support excitation, depending on the spatially varying components of incoherence, wave-passage and site-response effects. The substructure method which partitions the total soil-structure system into two substructures: the structural system and the soil system, is used to treat the soil-structure interaction problem. In order to investigate the soil-structure interaction effect on the response of cable-stayed bridges under multiple-support excitation, two-dimensional model of an existing bridge (Jindo Bridge) is used to represent the superstructure. To emphasize the relative importance of the spatial variability effects of the earthquake ground motion, bridge responses are determined for the fixed base bridge model which neglects the soil-structure interaction (no SSI) effect and for the bridge model which includes the soil-structure interaction (SSI) effect. It is noticed that, the dynamic bridge responses calculated for the multiple-support case reflecting the wave-passage effect are usually much larger than those of the responses obtained for the cases of incoherence and site-response effects. It is also observed that for specific response quantities, the responses obtained for the soil-structure interaction cases can be overestimated or underestimated if compared with the fixed base cases. The parametric study of the relative importance of the soil-bridge interaction in the presence of spatial variability components of the ground motion shows that the multiple-support excitation and soil-structure interaction should be considered in the dynamic analyses of cable-stayed bridges.