•Effects of single (IP → OOP) and mutual (IP ↔ OOP) interaction of unreinforced MIs.•Effects of removal of MIs when collapse is induced by a combination of IP and OOP actions.•GIS aided structural mapping so as to represent typical residential infilled buildings.•Simplified shear-type tridimensional scheme of infilled framed structures.•Extensive numerical investigation in order to explore effects of the different design parameters. In the aftermath of earthquakes poor seismic response was evidenced by non-structural elements such as enclosure masonry infills (MIs), characterized by a combination of in-plane (IP) and out-of-plane (OOP) damage mechanisms. The present work is aimed at identifying the effects of this mutual interaction on the nonlinear seismic behaviour of reinforced concrete (RC) framed structures. To this end, an extensive parametric study is carried out considering a spatial one-bay multi-storey shear-type model with MIs constituted of two leaves of clay hollow bricks, which is assumed as equivalent to infilled RC framed buildings. An extensive GIS aided structural mapping of the town of Rende (Italy) is adopted in order to obtain benchmark models as close to real structures as possible, focusing on total height, in plan dimensions and maximum and minimum bay lengths of the buildings. The dependence of the results on the variation of the following design parameters is considered for the i-th cluster of buildings characterized by the same number of storeys: i.e. fundamental vibration period; behaviour factor of the bare structure; aspect ratio of MIs, defined as the ratio between the panel length and height. A five-element macro-model comprising four (diagonal) nonlinear beams and one (horizontal) central nonlinear truss for the prediction of the OOP and IP behaviour of MIs, respectively, is first implemented in a homemade computer code. The proposed algorithm addresses the issue of the nonlinear mutual interaction of MIs by modifying stiffness and strength in the OOP direction on the basis of simultaneous or prior IP damage and vice-versa. A lumped plasticity model describes the inelastic behaviour of the RC frame members. Finally, a review of the current Italian, European and American seismic code provisions is performed by means of comparison with results of nonlinear dynamic analyses. To this end, bidirectional spectrum-compatible accelerograms are considered at ultimate limit states.