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This study utilizes large-scale shake table test to investigate the seismic performance of an isolated bridge with lead rubber bearings crossing an active fault. Two transverse restraining systems with and without shear keys are tested by applying spatially varying ground motions. It is shown that the near-fault span exhibits larger bearing displacement than the crossing-fault span. Bridge piers away from the fault rupture are more vulnerable than those adjacent to the fault rupture by attracting more seismic demand. It is also verified that the shear keys are effective in restraining the bearing displacement on the near-fault span, particularly under the large permanent ground displacement.