Biological processes often depend on protein–ligand binding events, yet accurate calculation of the associated energetics remains as a significant challenge of central importance to structure-based drug design. Recently, we have proposed that the displacement of unfavorable waters by the ligand, replacing them with groups complementary to the protein surface, is the principal driving force for protein–ligand binding, and we have introduced the WaterMap method to account this effect. However, in spite of the adage “nature abhors vacuum,” one can occasionally observe situations in which a portion of the receptor active site is so unfavorable for water molecules that a void is formed there. In this paper, we demonstrate that the presence of dry regions in the receptor has a nontrivial effect on ligand binding affinity, and suggest that such regions may represent a general motif for molecular recognition between the dry region in the receptor and the hydrophobic groups in the ligands. With the introduction of a term attributable to the occupation of the dry regions by ligand atoms, combined with the WaterMap calculation, we obtain excellent agreement with experiment for the prediction of relative binding affinities for a number of congeneric ligand series binding to the major urinary protein receptor. In addition, WaterMap when combined with the cavity contribution is more predictive than at least one specific implementation [Abel R, Young T, Farid R, Berne BJ, Friesner RA (2008)J Am Chem Soc130:2817–2831] of the popular MM-GBSA approach to binding affinity calculation.