The energy of dimerization of two N-methylacetamide (NMA) molecules in vacuum is calculated using density functional theory. Natural orbital analysis suggests that the dimerization energy of -6.6 kcal/mol is predominantly due to the (N-H⋯O=C) donor-acceptor interaction. The gas phase to water hydration free energies and the free energies of transfer from the aqueous phase to liquid alkane of hydrogen bonded, (N-H⋯O=C), and nonbonded, (N-H,O=C), groups are calculated using a continuum solvent model. On the basis of these calculations, we estimate the free energy of forming an amide hydrogen bond in the context of the NMA dimer in water and in liquid alkane as ∼-1 and ∼-5 kcal/mol, respectively. The relevance of these calculations to processes such as protein folding and membrane insertion of proteins is discussed.