The paper addresses the problem of determining the mechanical characteristics of an orthotropic slab that best represents the in-plane behavior of a complex reinforced concrete (RC) floor system. To represent the structural behavior of the real RC floor, a reference model composed of solid finite elements is developed. The mechanical parameters of the equivalent orthotropic slab are determined by different homogenization techniques. In particular, two numerical algorithms and an analytical procedure to derive the elastic parameters of the equivalent slab representing the in-plane behavior of a single floor cell are proposed. Then, to determine which homogenization technique best predicts the structural behavior, representative one-story and six-story structures are modeled using both the equivalent slabs obtained using the three proposed techniques and the reference floor model. A discussion of the suitability of modeling floor in-plane flexibility taking account of only the top RC slab, for the considered case studies, is also provided.