An increasing number of bridges have been built in earthquake zones, alonged with rapid development of high-speed railway. Their seismic behaviors attract researchers’ attention now. The steel shear keys as falling-off prevention measures have been used widely in 32m simply-supported box girder bridges on high-speed railways in China. To allow for transverse temperature movement, the shear keys are placed with a slight gap from the girders. However, out-of-phase vibrations between superstructures and substructures result in nonlinear eccentric pounding between bearing base and steel shear keys if the relative displacements exceed their initial gaps. The aim of this paper is to analyze the effect of eccentric pounding on elasto-plastic behavior of a simply-supported concrete box girder bridge under transverse earthquake, and evaluate the seismic performance of falling-off prevention measures. The effect of cushion block on seismic response has been studied. The results of the study indicate that a bridge column occur plastic deformation and suffer residual displacements due to eccentric pounding, and simple analysis in elastic range may result in nonconservative results. The lateral shear keys play a key role in limiting girder displacements. By setting hardwood blocks between steel shear keys and bearing base, the pounding forces can be appropriately reduced, and the lateral seismic performance of bridge can be effectively improved