By using the van't Hoff and Gibbs equations, the thermodynamic functions of Gibbs energy, enthalpy, and entropy of solution for procaine HC1 in ethanol + water cosolvent mixtures were evaluated from solubility data determined at temperatures from (278.15 to 308.15) K. The drug solubility was greatest in neat water and lowest in neat ethanol at all of the temperatures studied. This behavior showed the negative cosolvent effect for this electrolyte drug in this solvent system. By means of enthalpy entropy compensation analysis, a nonlinear Delta H(soln)(0-app) versus Delta G(soln)(0-app) plot with a positive slope from neat ethanol up to 0.10 mass fraction of water and negative from 0.10 to 0.30 mass fraction of water was obtained, whereas from this composition up to neat water a positive slope was obtained again. Accordingly to this result and to the transfer properties, it follows that the dissolution process of this drug in ethanol-rich and water-rich mixtures is enthalpy-driven, whereas between 0.10 and 0.30 mass fraction of water, the process is entropy-driven.