In order to investigate the seismic performance of multi-span cable-stayed bridges with tall piers, taking a five-span cable-stayed bridge with 178 m piers as an example, the finite element model of the bridge was developed and both the geometric and material nonlinearities were considered. 80 long-period and short-period ground motions were selected to conduct the nonlinear time history analysis. Based on 4 kinds of engineering demand parameters of cable-stayed bridges, the efficiency, the practicality and the proficiency of 9 kinds of ground motions intensity measures (IMs) were evaluated using the regression analysis method, and the selection suggestion of IMs was proposed. Moreover, the damage indexes of various components including bearing system, tower, deck and cable were defined according to the damage characteristic of bridge. Based on the fragility method, component fragility curves were developed. The vulnerable location of each kind of components was determined and the damages of various components were compared. Furthermore, design considerations for improving the seismic performance of the cable-stayed bridge with tall piers were proposed. The results show that the optimal IMs of regular bridges are unfit for multi-span cable-stayed bridges with tall piers to predict seismic response. Depending on different cases, spectral acceleration at first frequency and peak spectrum displacement are suitable for this kind of bridge. The bearing system, deck and cables present higher damage probability than towers under longitudinal ground motions. The damages of 1/4 and 3/4 mid-span of deck are serious. The damages of short cable in the side-span and long cable in the mid-span are serious amongst all the cables. As the damages of various components are mainly caused by the deformation of bridge, and the damages of tower are relatively slight, it's more important to control the displacement of bridge than inner force of tower while designing multi-span cable-stayed bridges with tall piers. © 2017, Editorial Department of China Journal of Highway and Transport. All right reserved.