Past earthquakes have repeatedly shown that damage to masonry infills can produce large economic losses and even jeopardize human lives. Nevertheless, in current design practice masonry infills are ignored, while available macro-models for nonlinear analysis focus the attention on the In-Plane (IP) behavior of masonry infills only, while neglecting the Out-Of-Plane (OOP) collapse mechanism. The main objective of this study is to investigate the seismic performance of RC frame buildings accounting for the interaction between IP and OOP behavior of masonry infills. To this end, a suitable nonlinear model, able to capture the IP stiffness and strength reduction due to the OOP displacement demand (and vice versa) is implemented. The selected model incorporates a routine that removes infills from the structural model when either IP or OOP collapse occurs. Different building models, representative of typical residential buildings, realized in Italy (and other European countries) from 50's to 90's, are examined through nonlinear response-time history analysis at different earthquake intensity levels, with return period ranging from 30 to 5000 years. Two alternative infill configurations (single layer and double layer with inner cavity) are considered, in accordance with the construction practice of the time. The comparison between the models with and without IP/OOP interaction points out the relevance of the OOP behavior towards an accurate evaluation of the seismic performance of RC frame buildings. A set of fragility curves is tentatively proposed, for different building performance levels, ranging from immediate occupancy to life safety. Keywords Seismic performance assessment • RC frame buildings • Masonry infill walls • In-plane/out-of-plane interaction • Nonlinear response time-history analyses * D.