The solution behavior of ethyl p-tert-butylcalix[5]arene pentanoate, EtCalix(5), in various protic and aprotic solvents has been assessed from the standard Gibbs energies of transfer of this ligand from acetonitrile to other solvents. These data were derived from solubility measurements of EtCalix(5) in different media. It is concluded that in solvents in which metal cation salts are predominant as ionic species in solution (within a low concentration range), the solvation of the ligand will not contribute significantly to the thermodynamics of cation complexation as a result of the medium effect. Various analytical techniques were used to identify the sites of ligand-cation interaction (1H NMR) and the composition (conductance and calorimetric measurements) of the metal-ion complexes in the various solvents. Titration calorimetry (direct and competitive) was used to thermodynamically characterize the cation binding ability of EtCalix(5) and gain quantitative information on the complex stability and the factors controlling it. Given the large bulk of data reported in the literature wrongly placed under the thermodynamic umbrella, particular emphasis is made about the need of identifying the process taking place in solution prior to proceeding with its thermodynamic characterization. The results are compared with those for the ethyl ester derivative of the cyclic tetramer, EtCalix(4). It is concluded that in moving from EtCalix(4) to EtCalix(5), (i) the selectivity of the latter for cations is swallowed toward the larger cations and (ii) although the number of binding sites increases, these are not able to exert the efficient control upon the ligand-cation binding ability as that found for the tetramer ester and these cations in these solvents.