Abstract: The foundation soil profile and corresponding consistent input motion, simulation of pile foundation, design seismic motion and the input level are the most important influence factors on the seismic response analysis of NI buildings with pile foundation. Base on the site soil properties of a typical non-bedrock nuclear power plant, the seismic response analysis model were developed with piles, soil and NI buildings. The equivalent linearization method was introduced to consider the nonlinear dynamic properties, and the development of soil profile and corresponding consistent input motion were proposed. The influences of simulation method of pile foundation, design seismic motion and input level on the seismic response of NI buildings with pile foundation were studied. The research showed that, the input motion should be consistent with the soil profiles used in seismic analysis of non-bedrock NI building; piles might be modeled by solid element which could simulate the seismic response more accurately; and there was small influence of equivalent seismic motion at different input level on the seismic response of NI building, but influence are significant due to the different design seismic motion at different level. The research works are of great importance to the design of nuclear island with pile foundation, and also the site selection of non-bedrock nuclear power plant.