Because a smart isolation system cannot be used as a base isolation system for tall buildings, top-story or mid-story isolation systems are required. In this study, adaptability of a smart top-story isolation system for reduction of seismic responses of tall buildings in regions of low-to-moderate seismicity has been investigated. To this end, 20-story example building structure was selected and an MR damper and low damping elastomeric bearings were used to compose a smart base isolation system. Artificial earthquakes generated based on design spectrum of low-to-moderate seismicity regions are used for structural analyses. Based on numerical simulation results, it has been shown that a smart top-story isolation system can effectively reduce both structural responses and isolation story drifts of the building structure in low-to-moderate seismicity regions in comparison with a passive top-story isolation system.