This paper evaluates and discusses the seismic response of unreinforced masonry buildings accounting for soil-foundation-structure interaction. A new strategy to model soil-foundation-structure interaction is firstly developed adopting a lumped parameters approach. A case study masonry building is selected, together with the foundation layout and soil profile. Lumped parameters models for the foundation of each masonry panel are then calibrated from 3D frequency domain analysis and applied at the base of the considered building, modelled by means of an equivalent-frame strategy. The lateral capacity of the entire building is assessed by pushover analyses, also allowing the estimation of relevant thresholds of a properly selected engineering demand parameter. Multi-stripe nonlinear dynamic analyses, carried out for different earthquake’s return periods, are finally performed to define the demand. Results obtained allow to assess the building’s performance and its modification due to the consideration of soil-foundation-structure interaction.