An isothermal titration microcalorimetry (ITC) study on the supramolecular complex formation between carboxylates and ammonium-squaramido based receptors at different ethanol:water proportions is reported. The results obtained show that the formation enthalpy sign of a supramolecular complex in a water-ethanol binary mixture can be influenced by the proportion of the cosolvent. Moreover there is an enthalpy-entropy compensation process in the supramolecular complex formation; in poor water mixtures the process is endothermic, whilst in reach water mixtures the process is exothermic. This behavior is mostly due to the intrinsic nature of the mixture between water and ethanol, and particularly the process of solvation and desolvation of receptor, substrate and complex. When this study is repeated with binary mixtures of water-methanol and water-DMSO it is observed that the nature of the organic solvent affects the results. While the mixture water-methanol has a behavior similar to water-ethanol mixture, the water-DMSO mixture shows clear differences. In order to check this compensation process, Delta Cp values are calculated at two different proportions water-ethanol, and they are consistent with an enthalpy-entropy compensation process similar to that described by the inclusion process for certain hydrophilic cyclodextrines. The results obtained show that the enthalpy-entropy compensation detected in the supramolecular complex formation between carboxylates and ammonium-squaramido receptors is independent of the spacer used, and more dependent on the microscopic nature and proportion of the binary mixture. (C) 2013 Elsevier B.V. All rights reserved.