Reinforced concrete (RC) frames with masonry infills can be encountered all over the world, especially in earthquake prone regions. Although masonry infills are usually not considered in the design process, in the case of seismic loading they are subjected to in-plane and out-of-plane forces that can act separately or simultaneously. In recent earthquakes it was observed that seismic loads can severely damage masonry infills or even cause their complete collapse, especially when the loads act simultaneously. Due to this, effects of interaction of in-plane and out-of-plane loads on seismic performance of masonry infills have received more attention recently. However, most of studies focus only on fully infilled frames, even though openings, such as windows and doors are essential parts of infills that substantially affect the seismic response of masonry infills. Therefore, this article presents the results of a comprehensive experimental study on nine full-scale traditional masonry RC frames infilled with modern hollow clay bricks for configurations with and without window and door openings under separate, sequential and combined in-plane and out-of-plane loading. Based on the results, a detailed comparison and interpretation for the different infill and loading configurations is presented. The test results clearly show the unfavourable influence of openings and combined loading conditions as well as the importance of the quality of execution of the circumferential mortar joint between infill and frame. The new findings can be used as a basis for the required development of innovative solutions to improve significantly the seismic performance of RC frames with masonry infills.