Abstract This paper presents an experimental study of the seismic performance of a category of reinforced concrete (RC) frame with weak infill panel and the complicated interaction between bounding frame and infill panel at different loading stages. Large-scale infilled RC frame specimens, which were fabricated to simulate those in as-built RC frame buildings designed in accordance with the provisions of Chinese seismic code (GB50011-2001), were tested under reversed cyclic loading. Particular emphasis was placed on the influence of the masonry materials and aspect ratio of infill walls on the hysteretic characteristics of the infilled frames. Three types of masonry infill were used, which included solid clay bricks (SCB), hollow concrete blocks (HCB) and aerated concrete blocks (ACB). The test results indicated that the bounding frames of infilled frame specimens had the same failure mode as the bare frame. These infilled frames exhibited superior seismic performance to the bare frame in terms of strength and energy dissipation capacity. The experiment showed the complicated interaction between bounding frame and infill panel as well as the failure mechanism of frames with weak infill. Moreover, HCB infill panels incurred the most serious damage amongst the infills, which may jeopardise the in-plane and out-plane stability of infill walls. Bounding frame bore a greater internal force than bare frame, especially at the end of columns, which affected the failure mode of the bounding frame. It is proposed to enlarge the moment and shear design values of columns to consider the local effect of infill on bounding frames in design practice. Based on the concept of the multi-line defence against earthquakes, it is suggested that infilled frames should be designed with the ‘strong frame-weak infill’ principle, in which frame and weak infill will form a two-line system of defence against earthquakes.