This paper describes a systematic study of the thermodynamics of association of bovine carbonic anhydrase II (BCA) and para-substituted benzenesulfonamides with chains of oligoglycine, oligosarcosine, and oligoethylene glycol of lengths of one to five residues. For all three of these series of ligands, the enthalpy of binding became less favorable, and the entropy less unfavorable, as the chain length of the ligands increased. The dependence on chain length of the enthalpy was almost perfectly compensated by that of the entropy; this compensation resulted in dissociation constants that were independent of chain length for the three series of ligands. Changes in heat capacity were independent of chain length for the three series and revealed that the amount of molecular surface area buried upon protein-ligand complexation did not increase with increasing chain length. Taken together, these data refute a model in which the chains of the ligands interact hydrophobically with the surface of BCA. To explain the data, a model is proposed based on decreasing "tightness" of the protein-ligand interface as the chain length of the ligand increases. This decreasing tightness, as the chain length increases, is reflected in a less favorable enthalpy (due to fewer van der Waals contacts) and a less unfavorable entropy (due to greater mobility of the chain) of binding for ligands with long chains than for those with short chains. Thus, this study demonstrates a surprising example of enthalpy/entropy compensation in a well-defined system. Understanding this compensation is integral to the rational design of high-affinity ligands for proteins.