The complexes of human carbonic anhydrase II (CA; EC 4.2.1.1) with the competitive inhibitors N-(4-sulfamylbenzoyl)glycine methyl ester (SBG), N-(4-sulfamylbenzoyl)benzylamine (SBB), and N-[N-[N-(4-sulfamylbenzoyl)glycyl]glycyl]glycine benzyl ester (SBG(3)) have been studied by X-ray crystallographic methods at limiting resolutions of 2.0, 2.3, and 2.4 Angstrom, respectively. Although the sulfonamides binding modes are similar in all three complexes, the hydrophobic tail of SBB and the oligoglycine tails of SBG and SBG(3) wrap across a hydrophobic patch in the enzyme active site with varying degrees of van der Waals contact surface area, and differences in enzyme-inhibitor contact are correlated with differences in affinity (Jain, A.; Huang, S. G.; Whitesides, G. M. J. Am, Chem. Sec., preceding paper in this issue). Importantly, this work illuminates some of the structural determinants of affinity in the CA active site. Moreover, this work demonstrates that it is possible to design an oligopeptide which binds to a protein surface not predesigned to do so.