Abstract <p>The protonation constants of cryptand[2.2] in aqueous dimethyl sulfoxide solutions were determined in the DMSO concentration range of 0.0–0.9 mole fractions by potentiometric titration at <i>T</i> = 298 K. It was established that at increased concentrations of dimethyl sulfoxide in solution, the equilibrium constants of the reactions of formation of mono- and diprotonated cryptand[2.2] change as extrema with a minimum. A comparison of the results with the literature data demonstrates that the dependence of the protonation constants on the composition of the water–dimethyl sulfoxide solvent behaves in a similar way for the majority of nitrogen-containing compounds. The protonation constants of cryptand[2.2] in an anhydrous dimethyl sulfoxide solution were estimated by calculation.</p>