The in-plane flexibility of floor-slab systems has been observed to influence the seismic response of many types of reinforced concrete buildings. The assumption of rigid floor diaphragms is often used to simplify engineering analyses without significant loss in the accuracy of seismic response prediction for most buildings. However, for certain classes of structures, such as long and narrow buildings (especially with dual-braced lateral load-resisting systems), and buildings with horizontal (T- or L-shaped) or vertical (setbacks or cross-walls) offsets, the effect of diaphragm flexibility cannot be disregarded. Moreover, if the floor slab panels experience cracking or yielding due to pronounced in-plane distortions, the seismic response of the entire building system may be significantly altered. This paper presents a simplified macromodeling scheme to incorporate the effect of inelastic floor flexibility in the seismic response analysis of RC buildings. The slab model includes effects of both in-plane flexure and shear. The inelastic behavior of diaphragms is emphasized through a study of narrow rectangular buildings with end walls. The study shows that the in-plane deflections of floor slabs impose a larger demand on strength and ductility of flexible frames than predicted values using the assumption of rigid or elastic slabs. These demands may in turn lead to a failure of the gravity-load supporting system. A quantitative estimate of this effect is presented in terms of the floor aspect ratios.