Alcoholysis of amides on the CeO(2)surface is investigated from density functional theory (DFT)computations, in situ FT-IR spectroscopy, and catalytic studies. The thermodynamically stable amide bonds are effectively activated by the CeO2 catalyst under mild conditions in contrast to other metal oxide catalysts. DFT calculations demonstrated that acetamide adsorbed on the CeO2 surface is attacked by lattice oxygen to give a tetrahedral intermediate in the rate-determining step of the most favorable pathway. This is consistent with the experimental finding that the activity of metal oxide catalysts increases with an increase of the base strength of the catalyst. The strong base sites of CeO2 are the most important factor for the high reactivity. Interestingly, the nucleophilic attack of lattice oxygen is further assisted by the moderately strong Ce4+ Lewis acid sites. Our computational results show that the high reactivity is ascribed to a catalytic interplay between the Lewis base and acid pair sites on the CeO2 surface.