Calculating protein–protein interaction energies is crucial for understanding protein–protein associations. On the basis of the methodology of mean-field potential, we have developed an empirical approach to estimate binding free energy for protein–protein interactions. This knowledge-based approach has been used to derive distance-dependent free energies of protein complexes from a nonredundant training set in the Protein Data Bank (PDB), with a careful treatment of homology. We calculate atom pair potentials for 16 pair interactions, which can reflect the importance of hydrophobic interactions and specific hydrogen-bonding interactions. The derived potentials for hydrogen-bonding interactions show a valley of favorable interactions at a distance of ≈3 Å, corresponding to that of an established hydrogen bond. For the test set of 28 protein complexes, the calculated energies have a correlation coefficient of 0.75 compared with experimental binding free energies. The performance of the method in ranking the binding energies of different protein–protein complexes shows that the energy estimation can be applied to value binding free energies for protein–protein associations. Proteins 2002;46:190–196. © 2001 Wiley-Liss, Inc.