The effects of soil-structure interaction on the seismic response of multi-span bridges are investigated by means of a modelling strategy based on the domain decomposition technique. First, the analysis methodology is presented: kinematic interaction analysis is performed in the frequency domain by means of a procedure accounting for radiation damping, soil-pile and pile-to-pile interaction; the seismic response of the superstructure is evaluated in the time domain by means of user-friendly finite element programs introducing suitable lumped parameter models take into account the frequency-dependent impedances of the soil-foundation system. Second, a real multi-span railway bridge longitudinally restrained at one abutment is analyzed. The input motion is represented by two sets of real accelerograms: one consistent with the Italian seismic code and the other constituted by five records characterized by different frequency contents. The seismic response of the compliant-base model is compared with that obtained from a fixed-base model. Pile stress resultants due to kinematic and inertial interactions are also evaluated. The application demonstrates the importance of performing a comprehensive analysis of the soil-foundation-structure system in the design process, in order to capture the effects of soil-structure interaction in each structural element that may be beneficial or detrimental. Copyright (C) 2011 John Wiley & Sons, Ltd.