The Los Santos scheelite skarn deposit, located in the province of Salamanca, northwest Spain, occurs in meter-thick strata-bound but irregular lenses of ≤1 km in length and contains a current total resource of 3.09 million metric tons (Mt) with an average grade of 0.54 percent WO3. It was produced by the metasomatic alteration of Upper Vendian-Lower Cambrian metasedimentary rocks and granitic rocks located in the western part of the Ávila batholith plutonic complex. Magmatic activity in the Los Santos zone comprises two intrusions, including biotite monzogranite (281–280 ± 6 Ma, granite I) and porphyritic biotite granodiorite-monzogranite (270-269 ± 6 Ma, granite II). The mineralized skarn distributed close to the intrusions occurred in two main stages: (I) prograde skarn, and (II) retrograde alteration of the stage I skarn. The prograde exoskarn is made up of a thick, almost monomineral mass of hedenbergite (Hd82–87), accompanied by grossular (Grs53–73) and scheelite rich in Mo (Sch I). Early mineralization is associated with granite I; thus, it is possible to recognize an endoskarn of calcic plagioclase and clinopyroxene developed over aplitic granite. The stage I skarn formed from H2O-rich fluids (XCO2 <0.1) with an upper temperature limit of 630°C at 0.18 to 0.2 GPa, a log fO2 of −21, and log fS2 ranging from −9.7 to −5.0. After the emplacement of granite II there was a late event characterized by pegmatites, dike swarms, breccia pipes, and intense fracturing associated with the retrograde alteration, which was superimposed on massive skarn. The retrograde skarn has a complex paragenesis that can be divided into two substages. In the first, subcalcic garnet formed, associated with the leaching of early scheelite and the precipitation of late scheelite poor in Mo (Sch II). There is also ferroactinolite, together with important amounts of anorthite, zoisite, apatite, titanite, quartz, and sulfides, mainly pyrrhotite. The first substage skarn formed from a complex H2O-(CO2 ± CH4 ± N2 ± C3H8)-(NaCl ± CaCl2) mixture with fO2 values of −23 and log fS2 ranging from −10 to −7. The data on fluid inclusions indicate that fluid boiling and immiscibility, at temperatures between 439° and 405°C and pressures ranging from 0.1 to 0.042 GPa, was a possible mechanism in the Sch II and sulfide deposition during the first substage of the retrograde alteration of the skarn. The second substage is characterized by the formation of clinozoisite, prehnite, quartz, calcite, chlorite, white mica, zeolite, and mineral phases belonging to the Bi-Te-Ag-S-Au system. The mineral assemblages indicate that the fO2 values are between −25.9 and −33.4 while log fS2 ranges from −10.6 to −6.3 for T <300°C. All the data suggest that the development of the Los Santos skarn represents the evolution of a magmatic-hydrothermal system. In this model, carbon-aqueous fluids would have been exsolved from the plutonic complex during its emplacement and crystallization. The gradual interaction of magmatic fluids at high temperatures with the graphitic rocks of the Schist-Greywacke Complex resulted in a reduction in ore fluids and higher CH4/CO2 ratios. The fluid associated with the last substage of the retrograde alteration of the deposit belongs to the H2O-NaCl system and suggests an influx of a surface-derived fluid.