This paper investigates the classical but yet intriguing question of modeling orthotropic RC floor systems endowed with lightening elements, by means of a uniform orthotropic slab, in order to describe accurately the building response under seismic loads. The simplified method, commonly adopted by engineers, based on the equivalence between the transverse stiffness of the RC elements of the real floor and those of the orthotropic slab is presented. A case study in which this simplified method is used is also provided. Then, an advanced finite elements (FE) based method to determine the elastic properties of the equivalent homogenized orthotropic slab is proposed. Based on the results obtained from the application of this method to a case study, a discussion on the adequacy of the simplified method is also provided.