A microcalorimetric study on the inclusion of monovalent and divalent metal cations by p-sulfonatocalix[4]arene was performed. The thermodynamic parameters for the complexation of alkali metal cations and Ag+ were obtained for the first time at neutral pH. The Na+ cation is routinely present as counterion of the calixarene in neutral aqueous solution, and this must be taken into account in the determination of the thermodynamic parameters for the complexation of Na+ and the other cations by considering a sequential or a competitive binding scheme. The ΔH° and ΔS° values show that the inclusion process is entropically driven, although an influence of the temperature on the complexation reaction indicates that the enthalpic term is also an important contributor. The results also reveal that enthalpy/entropy compensation balances the gain in one contribution against a corresponding loss in the other. The obtained thermodynamic data are in contrast to the results from previous microcalorimetric studies, which showed binding constants that were orders of magnitude smaller and complexations, which were in part enthalpically driven but which neglected the influence of the alkali metal counterions. Sequential and competitive binding schemes must be considered in determining the thermodynamic parameters for the complexation of Na+ and other metal cations, respectively, by p-sulfonatocalix[4]arene in order to take into account the Na+ cations that are routinely present as counterions of the calixarene in neutral aqueous solution (see figure), according to a microcalorimetric study. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.