A detailed chemometric analysis of ligand binding to domain-3A of human serum albumin is described. NMR and fluorescence data on a set of 889 chemically diverse compounds were used to develop a group contribution model based on 74 chemical fragments that is in good agreement with the experimental data (R2 = 0.94, Q2 = 0.90). The structural descriptors used in this analysis comprise a convenient look-up table for quantitatively estimating the effect that a particular group will have on albumin binding. This information can be valuable for optimizing a particular series of compounds for drug development.