A general theoretical development for the design and analysis of two-dimensional thermal stability surfaces of proteins is presented. The surfaces are generated from multiple excess heat capacity profiles (<delta Cp> vs T) obtained at varying concentrations of an interacting ligand. The energetics of both the intrinsic protein stability and the protein-ligand interaction are simultaneously resolved by employing statistical thermodynamic models in global linkage analysis. This formalism allows resolution of the intrinsic protein folding-unfolding parameters (enthalpy, entropy, and heat capacity changes) as well as the ligand interaction parameters (binding stoichiometry, enthalpy, entropy, and heat capacity changes). The theory has been applied to the case of ribonuclease A and its interaction with cytidine-2'-monophosphate. The accuracy of the thermodynamic parameters obtained by this approach compares within error with those parameters that can be obtained by direct measurements.