A denaturant-mediated protein unfolding model, which is different from already existing ones based on the assumption that denaturant competes for water molecules to interact and thus reduces water-protein interactions, which leads to unfolding phenomenon, has been developed with a detailed mathematical justification. Theoretical results suggested that the parameter (mu) obtained from the usual linear extrapolation model must be a linear function of the number of bound water molecules (n) on protein with a zero intercept. However, application of this theory to a set of proteins for which mu values for urea denaturation are already known showed that mu was a linear function of n but with a nonzero intercept. Finally this nonzero intercept was attributed to binding of denaturant to protein at n = 0. Detailed investigation of this factor showed that average equilibrium constant for binding of urea with aromatic side chains (generally nonpolar side chains) was kb ≈ 0.65 ± 0.45 mol-1, which agreed well with earlier experimental estimations, and also suggested that an integrated approach was necessary to avoid discrepancy in ΔGH2O estimated from different models.