Two fundamentally different thermodynamic approaches are in use to interpret or predict the effects of urea on biopolymer processes: one is a synthesis of transfer free energies obtained from measurements of the effects of urea on the solubilities of small, model compounds; the other is an analysis of preferential interactions of urea with a range of folded and unfolded biopolymer surfaces. Here, we compare the predictions of these two approaches for the contribution of urea-amide (peptide) interactions to destabilization of folded proteins by urea. For these comparisons, we develop independent thermodynamic analyses of osmometric and solubility data characterizing interactions of a model compound with urea (or any other solute) and apply them to all five model compounds (glycine, alanine, diglycine, glycylalanine, and triglycine) where both isopiestic distillation (ID) and solubility data in aqueous urea solutions are available. We use model-independent expressions to calculate mu(ex)(23) the derivative of the "excess" chemical potential of solute "2" (either a model compound or a biopolymer) with respect to the molality of solute "3" (urea). Analyses of ID data for these systems reveal significant dependences mu(ex)(23) on both m(2) and m(3), which must be taken into account in making comparisons with values of mu(ex)(23) obtained from solubility studies or from analyses of urea-biopolymer preferential interactions. Values of mu(ex)(23) calculated from model compound ID data at low m2 and m3 are directly proportional to the amount of polar amide (N, O) surface area, and not to any other type of surface. The proportionality constant in this limit, mu(ex)(23)/(RT center dot ASA) = (1.0 +/- 0.1) x 10(-3) angstrom(-2), is very similar to that previously obtained by analysis of urea-biopolymer preferential interactions ((1.4 +/- 0.3) x 10(-3) angstrom(-2)). This level of agreement for amide surface in the low concentration limit, as well as the absence of any significant preferential interaction of urea with Gly and Ala, reinforces the conclusion that the primary preferential interaction of urea with protein surface is a favorable interaction (resulting in local accumulation of urea) at polar amide surface, located mostly on the peptide backbone. However, mu(ex)(23) for interactions of urea with these model amides is found from both ID and solubility data to be urea concentration-dependent, in contrast to the urea concentration independence of the analogous quantity for protein unfolding.