The thermodynamics and energetics of the ion exchange of bovine serum albumin (BSA) at a cellulosic ion exchanger (Whatman QA52) have been studied. Equilibrium isotherm analysis allowed the determination of the thermodynamic equilibrium constants (K) for a range of pH. The heats of exchange of the BSA at Whatman QA52 were obtained by high-sensitivity titration microcalorimetry. A thermodynamic analysis procedure was developed allowing calculation of the standard free energy, the standard enthalpy, and the standard entropy of exchange. The results show that the relative contributions of the enthalpy and entropy change radically depend on the solution conditions. The knowledge of these thermodynamic properties provided useful insights into the relative importance of the factors contributing to the overall ion-exchange process. This assessment hence provides a basis for guidelines for more effective separation and for establishing a more practical model for theoretical prediction of ion-exchange performance.