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Significant amounts of blast furnace slag (BFS) are generated daily as by-product from iron and steel industries. This waste material usually has interesting physical properties and mineralogical and chemical composition, which can be useful as granular aggregate in the production of hot mix asphalt (HMA). In this study, an experimental program was designed to evaluate the effect on the resistance of a HMA due to the replacement (in mass and volume) of the coarse fraction of a natural aggregate (type limestone; LS) by a BFS. Total aggregate replacement was also evaluated. The mechanical properties were evaluated by carrying out the following tests: Marshall stability, indirect tensile strength (ITS), Cantabro abrasion, resilient modulus, permanent deformation, and fatigue resistance. Water sensitivity or moisture damage was evaluated by determining the ratio of indirect tensile strength (TSR) in wet and dry conditions. X-ray diffractometry (XRD), X-ray fluorescence (XRF) tests, and imaging processing in a scanning electron microscope (SEM) were carried out on particles of LS and BFS. The results revealed a remarkable enhancement in the properties of the HMA mixture when the coarse fraction of the LS was replaced in volume by BFS. When such a replacement was made in mass, the adhesive properties of the asphalt-aggregate system worsened. Total replacement of the LS led to unsatisfactory mechanical behavior. [ABSTRACT FROM AUTHOR]