This study investigated the effect of soil-structure interaction (SSI) on the response of base-isolated buildings. Seismic isolation can significantly reduce the induced seismic loads on a relatively stiff building by introducing flexibility at its base and avoiding resonance with the predominant frequencies of common earthquakes. To provide a better understanding of the movement behavior of multi-story structures during earthquakes, this study analyzed the dynamic behavior of multi-story structures with high damping rubber bearing (HDRB) behavior base isolation systems that were built on soft soil. Various models were developed, both with and without consideration of SSI. Both the superstructure and soil were modeled linearly, but HDRB was modeled non-linearly. The behavior of the specified models under dynamic loads was analyzed using SAP2000 computer software. Erzincan, Marmara and Duzce Earthquakes were chosen as the ground motions. Following the analysis, the displacements, base shear forces, top story accelerations, base level accelerations, periods and maximum internal forces were compared in isolated and fixed-base structures with and without SSI. The results indicate that soil-structure interaction is an important factor (in terms of earthquakes) to consider in the selection of an appropriate isolator for base-isolated structures on soft soils.