The solution enthalpy (ΔHsoln0) of lidocaine−HCl (LC−HCl) and procaine−HCl (PC−HCl) in water was determined by isoperibolic solution calorimetry at 298.15 K. It was found that ΔHsoln0 for LC−HCl diminishes as the drug concentration increases, whereas the behavior was the opposite for PC−HCl. On the other hand, the calorimetric values obtained as a function of the drug concentration were significantly different with respect to those calculated by using the van't Hoff method, based on solubility determinations at several temperatures. It was demonstrated that the van't Hoff method is not fully reliable for the determination of ΔHsoln0 values in the specific case of highly soluble organic hydrochloride salts. The observed phenomena could be explained by the presence of strong solute−solute interactions at high salt concentrations, in addition to the respective solute−solvent and solvent−solvent interactions.