Framed structures are usually infilled with masonry walls. They may cause a significant increase in both stiffness and strength, reducing the deformation demand and increasing the energy dissipation capacity of the system. On the other hand, irregular arrangements of the masonry panels may lead to the concentration of damage in some regions, with negative effects; for example soft story mechanisms and shear failures in short columns. Therefore, the presence of infill walls should not be neglected, especially in regions of moderate and high seismicity. To this aim, simple models are available for solid infills walls, such as the diagonal no-tension strut model, while infilled frames with openings have not been adequately investigated. In this study, the effect of openings on the strength and stiffness of infilled frames is investigated by means of about 150 experimental and numerical tests. The main parameters involved are identified and a simple model to take into account the openings in the infills is developed and compared with other models proposed by different researchers. The model, which is based on the use of strength and stiffness reduction factors, takes into account the opening dimensions and presence of reinforcing elements around the opening. An example of an application of the proposed reduction factors is also presented.