Leaching of uranium-fertile granites represents a major source of uranium, as uraninite is easily dissolved in oxygenated aqueous solutions. This phenomenon is well documented at surface conditions, but remains poorly documented for granites at depth. In this study, we propose that surface-derived oxidized hydrothermal fluids leached uranium from uraninite in the Questembert peraluminous granite at temperatures greater than ~70° to 160°C. This Variscan synkinematic granite is characterized by widespread and pervasive development of vertical and permeable C-S structures. These structures likely facilitated the infiltration of oxidized hydrothermal fluids from the surface, their circulation at depth, and the subsequent fluid-rock interaction in the granite. Published oxygen isotope data shows that it has undergone subsolidus fluid-rock interaction, dated between 312 and 303 Ma by 40Ar/39Ar analyses on muscovite. These interactions were responsible for the concomitant decrease of the feldspar δ18O values together with uranium leaching. Mass-balance calculations suggest that this hydrothermal event could have liberated several hundred thousand tonnes of uranium from the Questembert granite. The liberated uranium may have been dispersed in Early Permian intramountainous basins and therefore disseminated over large areas. This study emphasizes that the efficiency of uranium leaching may be directly related to the extent of subvertical structure development in granites emplaced along strike-slip shear zones, which allow for downward infiltration of oxidized surface-derived fluids. A specific and systematic sampling is required to better constrain the proposed model.