Solution enthalpies of 18-crown-6 have been obtained for a set of 14 protic and aprotic solvents at 298.15 K. The complementary use of Solomonov´s methodology and a QSPR-based approach allowed the identification of the most significant solvent descriptors that model the interaction enthalpy contribution of the solution process (ΔintHA/S). Results were compared with data previously obtained for 1,4-dioxane. Although the interaction enthalpies of 18-crown-6 correlate well with those of 1,4-dioxane, the magnitude of the most relevant parameters, pi* and beta, is almost three times higher for 18-crown-6. This is rationalized in terms of the impact of the solute’s volume in the solution processes of both compounds.