The thermodynamic analysis and preferential solvation of the solubility of sulphanilamide (SA) in five cosolvent mixtures (ethanol + water; 1,4-dioxane + water, acetonitrile + water, dimethyl-sulphoxide + water, and dimethylsulphoxide + water) are presented. The thermodynamic functions are calculated employing the Gibbs and van´t Hoff equations, and the analysis of preferential solvation is developed by inverse Kirkwood–Buff integrals method. The solubility process is endothermic, with entropic favouring in all cases. Finally, according to the solvation parameter, SA is solvated preferentially by water in more polar mixtures, and in DMF + W, and DMSO + W mixtures it is solvated by organic solvent. In the other mixtures (EtOH + W, DIOX + W, and MeCN + W) the SA is solvated by the organic solvent in intermediate mixtures and by water in the less polar mixtures.