A novel efficient HFIP-catalyzed synthesis of structurally diverse 2,2-difluoro-3-hydroxy-1,4-diketone derivatives from readily available glyoxal monohydrates and difluoroenoxysilanes is described. This convenient protocol is induced by the distinctive fluorine effect of the reactants and the fluoroalcohol catalyst, which represents the first application of fluoroalcohol catalysis in a Mukaiyama aldol reaction.