Masonry infills are frequently employed as both outer and inner partitions in reinforced concrete (RC) frame structures due to their outstanding characteristics in terms of energy efficiency, fire resistance and sound isolation. However, common construction practice typically involves the mortar connection between masonry infills and RC frames. For this reason, the unforeseen frame-infill interaction takes part under seismic loading, which leads to severe and uncontrollable damage to masonry infills. This interaction also causes damage or even the collapse of the RC frames and thus of the whole structures. The poor performance of infilled RC frame structures in recent earthquake events is a strong motivation for the development of innovative engineering solutions, which aim to mitigate the detrimental effects of frame-infill interaction. This article introduces an innovative decoupling system founded on the concept of decoupling the RC frame from the masonry infill. The decoupling is achieved by inserting elastomeric material between the masonry infill and RC frame. The properly designed decoupling system allows infill activation only at high in-plane drifts. Simultaneously, it provides boundary conditions for seismic loads acting perpendicular to the infill plane. Firstly, the article explains the design of the masonry infill with the decoupling system and its installation. Afterwards, the results of small specimen tests carried out to determine the load-bearing capacity of the decoupling system are presented. Furthermore, the article discusses the findings of an extensive experimental campaign conducted on nine real-size RC frames with decoupled infills subjected to separate and combined in-plane and out-of-plane loadings. In addition to different loading types, various infill configurations are considered – solid infill, infill with centric window, and infill with centric door opening. Finally, the experimental results of RC frames with decoupled infills are compared with the experimental results of traditionally infilled RC frames, which were tested within the framework of the same project. The thorough evaluation and comparison of the experimental findings demonstrate the significant improvement of seismic performance of infilled RC frames if the decoupling system is applied.