A water-soluble cubic coordination cage (Hw) has been prepared, which is isostructural with a previously reported organic-soluble cage (H) apart from the hydroxy groups on the external surface which render it water-soluble. These two cages act as hosts for small organic molecules which bind via a combination of (i) hydrogen-bonding interactions with specific sites on the internal surface of the cages; (ii) non-polar interactions such as aromatic and van der Waals interactions between aromatic rings in the guest and the cage internal surface; and (iii) solvophobic interactions. By comparing ΔG° values for guest binding in water (using Hw) and MeCN (using H), and using pairs of related guests that differ in the presence or absence of an aromatic ring substituent, it is possible to construct thermodynamic cycles that allow quantification of the solvophobic contribution to binding. Specifically, this is the difference between the solvophobic contributions to ΔG° in water and MeCN associated with desolvation of both guest and the internal surface of the cage when complexation occurs. A highly consistent value of ca. −10 kJ mol−1 is determined for this solvophobic contribution to ΔG° associated with the aromatic ring in water compared to MeCN, which correlates very well with what would be expected based on the free energy changes associated with transfer of toluene from MeCN to water. Thus, all three contributions to guest binding listed above can be separately quantified. The ability to prepare related pairs of guests with the presence or absence of a wide range of substituents provides a potentially general way to quantify the solvophobic contributions to guest binding of these substituents.