Given　the　increase　of　nuclear　power　plants,　it　has　become　unavoidable　for　the　pile-supported　nuclear-island　buildings　to　be　constructed　on　the　coastal　deposits　potentially　influenced　by　strong　earthquakes.　The　coupling　influences　of　the　hysteresis　nonlinearity　of　soil　and　the　soil-pile-structure　interaction　(SPSI)　have　not　yet　been　considered　comprehensively　in　the　seismic　response　analysis　of　the　nuclear-island　building,　although　it　is　a　vital　issue.　On　the　basis　of　a　newly-developed　generalized　non-Masing　hysteretic　constitutive　model,　a　3D　integrated　simulation　method　is　proposed　to　evaluate　the　seismic　responses　of　the　pile-mat-founded　nuclear-island　building　system　subjected　to　multidirectional　earthquake　motions.　This　integrated　method　involves　an　explicit　parallel　algorithm　framework,　comprising　the　nuclear-island　building　modeling,　the　pile-mat　foundation　modeling,　the　inhomogeneous　soil　domain　modeling,　and　the　artificial　boundary　condition.　The　bedrock　records　of　near-field,　moderate-far　field　and　far-field　earthquake　scenarios　are　assumed　for　determining　the　bedrock　motions　of　the　ultimate　and　operational　safety　earthquakes.　For　an　actual　pile-mat-founded　AP1000　nuclear-island　building,　the　simulation　results　show　the　complexity　and　significance　of　the　coupling　effect　of　the　site,　the　tridirectional　earthquake　shaking,　and　the　secondary　nonlinearity　of　soil.　Such　a　complex　coupling　effect　significantly　increases　the　seismic　responses　of　the　pile-mat-founded　nuclear-island　building.　A　notable　finding　is　that　the　scenario　earthquakes　with　abundant　long　period　components　may　have　more　destructive　potential　to　the　pile-mat-founded　nuclear-island　buildings　than　the　scenario　earthquakes　with　characteristics　of　abundant　short　period　components　and　shorter　durations.　The　results　provide　insights　into　the　seismic　design　of　the　pile-mat-founded　nuclear-island　buildings,　which　could　guide　the　design　and　construction　of　such　similar　facilities　in　the　high　seismic　intensity　regions.