Experimental results of an unprecedented haloform-type reaction in which 4-alkyl-4-hydroxy-3,3-difluoromethyl trifluoromethyl ketones undergo base-promoted selective cleavage of the CO-CF(3) bond, yielding 3-hydroxy-2,2-difluoroacids and fluoroform, are rationalized using DFT (B3LYP) calculations. The gas-phase addition of hydroxide ion to 1,1,1,3,3-pentafluoro-4-hydroxypentan-2-one (R) is found to be a barrierless process, yielding a tetrahedral intermediate (INT), involving a DeltaG(r)(298 K) of -61.4 kcal/mol. The CO-CF(3) bond cleavage in INT leads to a hydrogen-bonded [CH(3)CHOHCF(2)CO(2)H...CF(3)](-) complex by passage through a transition structure (TS1) with a DeltaG()(298 K) of 20.8 kcal/mol and a DeltaG(r)(298 K) of 9.8 kcal/mol. This complex undergoes a proton transfer between its components, yielding a hydrogen-bonded [CH(3)CHOHCF(2)CO(2)...CHF(3)](-) complex. This process has associated with it a DeltaG()(298 K) of only 3.1 kcal/mol and a DeltaG(r)(298 K) of -43.3 kcal/mol. The CO-CF(2) bond cleavage in INT leads to a hydrogen-bonded [CH(3)CHOHCF(2)...CF(3)CO(2)H](-) complex by passage through a transition structure (TS3) with a DeltaG()(298 K) of 29.2 kcal/mol and a DeltaG(r)(298 K) of 25.1 kcal/mol. The lower energy barrier found for CO-CF(3) bond cleavage in INT is ascribed to the larger number of fluorine atoms stabilizing the negative charge accumulated on the CF(3) moiety of TS1, as compared to the number of fluorine atoms stabilizing the negative charge on the CH(3)CHOHCF(2) moiety of TS3. The solvent-induced effects on the two pathways, introduced within the SCRF formalism through PCM calculations, do not reverse the predicted preference of the CO-CF(3) over the CO-CF(2) bond cleavage of R in the gas phase.