Abstract By using the van't Hoff and Gibbs equations the thermodynamic functions free energy, enthalpy, and entropy of solution, mixing, and solvation of naproxen (NAP) in ethanol (EtOH) + water (W) cosolvent mixtures, were evaluated from solubility data determined at several temperatures. The solubility was greater in pure ethanol and lower in water at all temperatures studied. This result shows the cosolvent effect present in this system. The solvation of this drug in the mixtures increases as the EtOH proportion is also increased in the mixtures. By means of enthalpy–entropy compensation analysis, nonlinear versus compensation with negative slope from pure water up to 30% EtOH and positive slope from 30% EtOH up to 70% EtOH was obtained. Over 70% EtOH the behavior was more complex. Accordingly to these results it follows that the dominant mechanism for solubility of NAP in water-rich mixtures is the entropy, probably due to water-structure loosing by EtOH; whereas, over 30% EtOH the dominant mechanism is the enthalpy probably due to NAP solvation increase by EtOH molecules. Keywords: NaproxenSolubilitySolution thermodynamicsSolvation Acknowledgements We thank the DIB-DINAIN of the Universidad Nacional de Colombia (UNC) for the financial support. Additionally we thank the Department of Pharmacy of UNC for facilitating the equipment and laboratories used.