Why does urea weaken the hydrophobic effect? A classical theory proposed that urea breaks the water structure without association with the hydrophobic solutes. Yet this view contradicts a recent statistical mechanical approach which confirmed that urea does accumulate around proteins and the hydrophobic groups. The justification of the water structure hypothesis, however, is the positive hydrophobic enthalpy of transfer from water to urea solution. What, then, is the origin of the positive enthalpy of transfer? Here the Kirkwood-Buff theory of solution shows that the positive enthalpy can be attributed to the temperature-dependence of urea-solute interaction. Thus the positive enthalpy of transfer does not mean the lack of urea-hydrophobic association. (C) 2011 Elsevier B.V. All rights reserved.