This article deals with an experimental program to investigate the in-plane seismic behavior of steel frames with clay brick masonry infills having openings. Six large-scale, single-story, single-bay frame specimens were tested under in-plane cyclic loading applied at roof level. The infill panel specimens included masonry infills having central openings of various dimensions. The experimental results indicate that infill panels with and without openings can improve the seismic performance of steel frames and the amount of cumulative dissipated energy of the infill panels with openings, at ultimate state are almost identical. Furthermore, contrary to the literature, the results indicate that infilled frames with openings are not always more ductile than the ones with solid infill. It seems that the ductility of such frames depends on the failure mode of infill piers. This experimental investigation shows that infilled frames with openings experienced pier diagonal tension or toe crushing failure and have smaller ductility factors than those frames with solid infill. Furthermore, a simple analytical method is proposed to estimate the maximum shear capacity of masonry infilled steel frames with window and door openings.