Methonium (N+Me3) is an organic cation widely distributed in biological systems. As an organic cation, the binding of methonium to protein receptors requires the removal of a positive charge from water. The appearance of methonium in biological transmitters and receptors seems at odds with the large unfavorable desolvation free energy reported for tetramethylammonium (TMA(+)), a frequently utilized surrogate of methonium. Here, we report an experimental system that facilitates incremental internalization of methonium within the molecular cavity of cucurbit[7]uril (CB[7]). Using a combination of experimental and computational studies, we show that the transfer of methonium from bulk water (partially solvated methonium state) to the CB[7] cavity (mostly desolvated methonium state) is accompanied by a remarkably small desolvation enthalpy of just 0.5 +/- 0.3 kcal.mol(-1), a value significantly less endothermic than those values suggested from gas-phase model studies. Our results are in accord with neutron scattering measurements that suggest methonium produces only a minimal perturbation in the bulk water structure, which highlights the limitations of gas-phase models. More surprisingly, the incremental withdrawal of the methonium surface from water produces a nonmonotonic response in desolvation enthalpy. A partially desolvated state exists, in which a portion of the methonium group remains exposed to solvent. This structure incurs an increased enthalpic penalty of similar to 3 kcal.mol(-1) compared to other solvation states. We attribute this observation to the pre-encapsulation dewetting of the methonium surface. Together, our results offer a rationale for the wide distribution of methonium in a biological context and suggest limitations to computational estimates of binding affinities based on simple parametrization of solvent-accessible surface area.