The　paper　proposes　a　mega-substructure　inter-story　isolation　system,　in　which　the　substructure　is　designed　to　be　isolated　from　the　mega-structure　by　flexible　isolators.　A　simplified　analytical　model　of　the　mega-substructure　inter-story　isolation　system　is　developed,　and　the　governing　equation　of　the　new　inter-story　isolation　system　is　formulated.　Complex　mode　analysis　method　is　used　to　derive　the　random　response　of　mega-substructure　inter-story　isolationsyst　m.Anoptimalproc　dur　form　ga-substructur　int　r-storyisolationsyst　misputforwardonth　basis　of　NSGA　algorithms.　Numerical　simulation　shows　that　the　proposed　optimal　procedure　for　the　new　isolation　system　is　accurate　and　efficient.　Further　research　shows　that　with　increase　in　substructure　mass,　its　work　mechanism　is　changed　from　tuned　vibration　absorber　,　energy　dissipation　to　seismic　isolation.　Time　history　analysis　of　the　mega-substructureinter-　storyisolationsystem　showsthatbothdriftofprimarystructureandabsoluteaccelerationofsub-structure　are　attenuated　significantly.　In　contrast　with　traditional　mega-substructure　,　input　energy　,　kinetic　energy　,　disipated　energy　and　deformation　energy　in　mega-sub　structure　inter-story　isolation　system　are　greatly　reduced.