Reinforced concrete (RC) buildings with masonry infill walls are widely used in many countries all over the world. Although infills are considered as non-structural elements, they significantly change dynamic characteristics of RC frame structures during earthquake excitation. Recently, significant effort was spent on studying decoupled infills, which are isolated from the surrounding frame usually by adding a gap between frame and infill. In this case, the frame deformation does not activate infill wall, thus infills are not influencing the behaviour of the frame. This paper presents the results of the investigation of the behaviour of RC frame buildings with the INODIS system that decouples masonry infills from the surrounding frame. Effect of masonry infill decoupling was investigated first on the one-bay one-storey frame. This was used as a base for parametric study on the frames with more bays and storeys, as well as on the building level. Change of stiffness and dynamic characteristics was analysed as well as response under earthquake loading. Comparison with the bare frame and traditionally infilled frame was performed. The results show that behaviour of the decoupled infilled frames is similar to the bare frame, whereas behaviour of frames with traditional infills is significantly different and demands complex numerical models. This means that if adequate decoupling is applied, design of infilled frame buildings can be significantly simplified.