Proteins often bind other proteins in more than one way. Thus alternative binding modes is an essential feature of protein interactions. Such binding modes may be detected by X-ray crystallography and thus reflected in Protein Data Bank. The alternative binding is often observed not for the protein itself but for its structural homolog. The results of this study based on the analysis of a comprehensive set of co-crystallized protein–protein complexes show that the alternative binding modes generally do not overlap, but are spatially separated. This effect is based on molecular recognition characteristics of the protein structures. The results are also in excellent agreement with the intermolecular energy funnel size estimates obtained previously by an independent methodology. The results provide an important insight into the principles of protein association, as well as potential guidelines for modeling of protein complexes and the design of protein interfaces.