Two empirical indices accounting for the hydrophobic interaction are described. The first index is a "hydrophobic field-effect (Hf) index, "which indicates the hydrophobic nature of the binding site of a host molecule such as an enzyme, and the second index is a "hydrophobic correlation (Hc) index", which indicates the hydrophobic correspondency between a host molecule and its guest molecule such as a ligand. Furthermore, a method to calculate the surface area of a molecule is described, in which the molecular surface is treated as a set of area-preserving spherical triangles. The hydrophobic effects on the interaction between papain and its inhibitor benzyloxycarbonyl-L-phenylalanyl-L-alanyl-methylene (Z-Phe-Ala-CH2-), which is covalently bound to catalytic Cys Sγ of the enzyme, were investigated by using these indices. It is quantitatively shown that the binding sites interacting with the benzene rings of P2 Phe and P3 Z are more hydrophobic, while the site of the carbonyl group of P1 Ala is more hydrophilic. The substrate specificity of papain can be explained in part by these indices. Both the Hc and Hf indices are visualized by using computer graphics. These indices would be useful as quantitative structure-activity relationship (QSAR) parameters.