A stoichiometric displacement retention model for proteins based on hadro-phobic interaction chromatography (HIC) is presenter. Several methods were used to demonstrate that water is the displacing agent in this process. Salt not only affects the molar concentration of water of water, but also changes the conformation of proteins, hydro-phobic interaction forces and the number of awter moiecules in a series of hydrated protein molecules. An equation that relates the capacity foactor of proteins, K', to the water concentration and the stoichiometric displacement factor, Z (the number of water molecules required to displace a protein from ligands) was derived. The in-tercept of this equation, log I, contains a number of constants a number of constants tha relate to the affinity of protein to the ligands. There is a good linear relationship betwwen log k's and log [H2O] under different chromatographic conditions. Although Z and log I varied with pH, slope j 1.74, the logarithm of hte molar concentration of pure water. Hydrophobic interactions dominate the retention of proteins in HIC at high salt concentrations.