The purpose of this work was to investigate the origin of the different solubility pro®les of drugs against the polarity of solvent mixtures with a common cosolvent. Ni¯umic acid and caffeine where chosen as model drugs. The solubilities were measured at ®ve or six temperatures in aqueous (ethanol±water) and nonaqueous (ethyl acetate±ethanol) mixtures. The enthalpies of solution were obtained at the harmonic mean of the experimental temperature. Solid phase changes were analyzed using differential scanning calorimetry and thermomicroscopy. A single solubility maximum was obtained for ni¯umic acid against the solubility parameter of both mixtures that is not related to solid phase changes. In contrast, caffeine displays two maxima and anhydrous±hydrate transition occurs at the solubility peak in the amphiprotic mixture. The apparent enthalpies of solution of both drugs show endothermic maxima against solvent composition that are related to hydrophobic hydration. A general explanation for the cosolvent action in aqueous mixtures is proposed. The dominant mechanism shifts from entropy to enthalpy at a certain cosolvent ratio dependent on the hydrophobicity and the solubility parameter of the drug. Ni¯umic acid and caffeine show enthalpy±entropy compensation in ethanol±water, and this relationship is demonstrated for the ®rst time in nonaqueous mixtures. The results support that enthalpy± entropy compensation is a general effect for the solubility of drugs in solvent mixtures. The shape of the solubility curves is correlated with the compensation plots. The solubility peaks separate different enthalpy±entropy relationships that also differentiate the solubility behavior of the hydrate and the anhydrous forms of caffeine.