The paper presents the results of an experimental investigation assessing the influence of the openings typology and position on the cyclic response of masonry‐infilled reinforced concrete frames. The experimental program consisted of seven 2/3 scale square frame specimens infilled with hollow clay bricks, which were subjected to quasi‐static lateral cyclic tests up to large drifts. A reference bare frame was also tested for comparison. The specimens included solid infill walls, infills with door openings, and infills with window central and eccentric openings. The experimental responses of the specimens were analyzed in terms of strength, stiffness, energy dissipation capacity, and equivalent damping, and were compared to those of the reference bare frame and fully infilled frame. Results revealed a significant modification of the resisting mechanisms as a function of the typology and position of the openings with respect to the case of a fully infilled frame, although the lateral resisting capacity was not substantially modified. On the other hand, it was observed that the achievement of the limit state thresholds occurred at substantially different interstorey drifts, indicating different damage metrics. Simple regression analyses, based on the experimental results of this study and from the literature, were finally conducted to interpret the modification of the peak force and of the corresponding drift as a function of synthetic parameters defining the opening arrangement.