A novel set of protein descriptors has been developed to increase the understanding of protein behavior on chromatographic media. The protein descriptors are pH-dependent and based on electrostatic and hydrophobic properties of mainly the surface of the proteins as revealed by their three-dimensional structure. Interpretable and predictive quantitative structure property relationship (QSPR) models were then obtained for protein retention in ion exchange chromatography at different pH values. In most cases the calculated average surface potential could be directly related to retention times. Moreover, the high retention of human lactoferrin observed in cation exchange even at high pH values could be modeled by adding descriptors of the charge asymmetry.