The intrinsic solvent contribution to the free energy of protein-ligand interactions in solution is shown to be related to a free energy per unit area term, obtained from analysis of the solution to gas phase process, and the change in accessible area on association. Analysis of the free energy data on a per unit area basis for the solution to gas phase process leads to the conclusion that the aliphatic CH 2 group is only slightly intrinsically hydrophobic, δΔG°/ A ̊ 2 = 6 cal mol −1 A ̊ 2 , whereas the aromatic compound are actually intrinsically hydrophilic, δΔG°/ A ̊ 2 = -26 cal mol −1 A ̊ 2 . This leads to the conclusion that, for the interaction of benzene, naphthalene and anthracene with the binding site of α-chymotrypsin, the ligand-solvent free energy contribution is actually unfavorable. Since the protein-solvent contribution is small or unfavorable, the central conclusion is that the solvent contribution to protein-ligand interactions is small or unfavorable and that it is the protein-ligand non-bonded interactions that provide the driving force for association.