Abstract: Taking a five-story reinforced concrete frame structure as an example, the structural properties were compared and analyzed by using YJK and PERFORM-3D programs, and the seismic perfomance of the frame structure with multi-storey unbraced columns and a big opening on the first floor slab was studied. The research results showed that under frequent earthquakes, the natural vibration period of the multi-story frame structure was longer, and the elastic interstorey drift angles of the first floor and the second floor were increased by 10.3%. Under rare earthquakes, the base shear force of the structure had decreased, the floor displacement had increased, and the elastic-plastic interstorey drift angle of the first floor had increased by 16%. The opening led to the lateral resistance members of this layer and its adjacent layers to consume more energy than other layers, which resulted in more damage and stiffness degradation of the lateral resistance members. The maximum plastic tensile strain of steel bars in the multi-storey unbraced columns had increased by about 15% when there was an big opening, which reduced the ductile deformation capacity of the structure. Strengthening the reinforcement of the multi-storey unbraced columns according to the principle of proximity could significantly reduce the impact of aggravated damage of the multi-storey unbraced columns caused by the opening.