Based on the properties of multi-span simply supported girder bridges and rail system re straints on the high-speed railway, the rail-bridge into an organic whole model is established by considering rail, track slab, friction between rail and fasteners, and bridge structure. The nonlinear time history analysis method is adopted to research the influnce of rail system restraint on elasto-plastic seismic response of piers for selected spans. The results show that the effect of rail system restraint on elasto-plastic seismic response of multi-span simply supported girder bridge with relatively great differences among the height of adjacent piers is significant, so it is adviced for the case that the rail-bridge into an organic whole model should be adopted in elasto-plastic seismic response analysis.