Abstract Reinforced concrete frame structures with masonry infills often exhibit serious damage after earthquake events, as the infills are generally installed without additional constructive measures in contact to the reinforced concrete frame. The masonry infills constructed in this way experience an unplanned interaction with the surrounding RC frame and thus become part of the horizontal load-bearing system with in-plane loading. This interaction combined with seismically induced loads perpendicular to the infill panel often leads to total collapses of the masonry infills and heavy damages to the RC frames. This fact was the motivation to develop an innovative system for decoupling the RC frame and the masonry infill with a special profile made of elastomeric cellular material within the collaborative European research project INSYSME (Innovative Systems for Earthquake Resistant Masonry Enclosures in Reinforced Concrete Buildings). The profile allows relative displacements between the RC frame and the masonry infill and serves at the same time as a support for out-of-plane loads. The article first explains the design and installation of the system and provides an overview of the load bearing capacities determined through small specimen tests on the system components. Subsequently, fundamental experimental investigations on traditional and decoupled RC frames infilled with high thermal insulating clay bricks for separate and combined in-plane ‬and out-of-plane loading are presented. Based on a detailed evaluation and comparison of the test results, the performance and effectiveness of the developed system are illustrated.