We describe a statistical thermodynamic approach to analyzing urea-dependent volumetric properties of proteins. We use this approach to analyze our urea-dependent data on the partial molar volume and adiabatic compressibility of lysozyme, apocytochrome c, ribonuclease A, and alpha-chymotrypsinogen A. The analysis produces the thermodynamic properties of elementary ureaprotein association reactions while also yielding estimates of the effective solvent-accessible surface areas of the native and unfolded protein states. Lysozyme and apocytochrome c do not undergo urea-induced transitions. The former remains folded, while the latter is unfolded between 0 and 8 M urea. In contrast, ribonuclease A and alpha-chymotrypsinogen A exhibit urea-induced unfolding transitions. Thus, our data permit us to characterize ureaprotein interactions in both the native and unfolded states. We interpreted the urea-dependent volumetric properties of the proteins in terms of the equilibrium constant, k, and changes in volume, Delta V-0, and compressibility, Delta K-T0, for a reaction in which urea binds to a protein with a concomitant release of two waters of hydration to the bulk. Comparison of the values of k, Delta V-0, and Delta K-T0 with the similar data obtained on small molecules mimicking protein groups reveals lack of cooperative effects involved in ureaprotein interactions. In general, the volumetric approach, while providing a unique characterization of cosolventprotein interactions, offers a practical way for evaluating the effective solvent accessible surface area of biologically significant fully or partially unfolded polypeptides.