A seismic isolation system is one of the most effective control devices used for mitigating the structural responses due to earthquake loads. This system is generally used as a type of base isolation system for low- and mid-rise building structures. If the base isolation technique is applied to high-rise buildings, a lot of problems may be induced such as the movement of isolation bearings during severe wind loads, the stability problem of bearings under large compression forces. Therefore, a mid-story isolation system was proposed for seismic protection of high-rise buildings. Residence-commerce complex buildings in Korea have vertical irregularity because shear wall type and frame type structures are vertically connected. This problem can be also solved by the mid-story isolation system. An effective analytical method using super elements and substructures was proposed in this study. This method was used to investigate control performance of mid-story isolation system for residence-commerce complex buildings subjected to seismic loads. Based on numerical analyses, it was shown that the mid-story isolation system can effectively reduce seismic responses of residence-commerce complex tall buildings.