AbstractA primitive model for solvent denaturation is that the denaturant binds independently to sites exposed by the unfolding of the protein. For reagents like urea and guanidinium salts, this binding must be very weak since denaturation occurs only at very high concentrations. Standard formulas for very weak binding lead to thermodynamic inconsistencies. In this paper, binding by denaturants is treated as selective solvation. This introduces a factor of K 1 into the binding isotherm and binding free energy, where K is the equilibrium constant for selective interaction with the sites. This leads to a thermodynamically consistent description of the binding and the denaturation since, when K = 1, there is no selective interaction and no effect on denaturation, even in concentrated solutions where site occupancy is inevitable.