Seismic design for high-rise structures requires determining the expected base shear, inter-story drift of each story level, and structural elements internal forces. Dealing with the base of structures as a fixed support has many disadvantages and not always conservative. Soil-structure interaction (SSI) represents more realistic and accurate simulation to seismic response of structures as it evaluates the collective response of the structure, the foundation, and the subsurface lithology to a specified ground motion. Present study focuses on the direct approach of soil-structure interaction analysis of a three-dimensional high-rise reinforced concrete building over piled-raft foundation. Fully nonlinear numerical analysis using finite element method was utilized and verified to evaluate the seismic responses in the structure employing Plaxis 3D software. The effects of base flexibility (SSI) as well as increasing piles embedment depths on the seismic performance of high-rise structures are investigated.