The gas-phase acidities (DeltaG(acid)) of cis- and trans-2-tert-butyl-1,3-dithian-5 -ol (1 and 2, respectively) have been determined to be 354.9 +/- 1.2 and 350.2 +/- 2.8 kcal/mol, respectively, by using the Cooks' kinetic method and acid-base bracketing in a flowing afterglow-triple quadrupole apparatus. The difference in the acidities of these diastereoisomers is unexpectedly large (4.7 kcal/mol) and significantly greater than that of epimeric 4-methylcyclohexanols (DeltaDeltaG(acid) = 1.1 kcal/mol). The large difference is due to the unusually low acidity of 1, which is rationalized by an unfavorable electrostatic repulsion between the oxygen]one pairs of the corresponding axial alkoxide and the ring sulfur]one pairs. This interaction is not present in the conjugate base of 2, in which the negatively charged group is in an equatorial position. Density functional theory calculations (B3LYP/6-311+G(2d,p)) predict the axial 1,3-dithian-5 -oxide (C4H7S2O-) to be higher in energy than the equatorial 1,3-dithian-5 -oxide by 6.5 kcal/mol (298 K), in agreement with our hypothesis. The gasphase acidities of I and 2 are predicted by theory (same level as above) to be 365.1 and 356.2 kcal/mol, respectively, corresponding to a DeltaDeltaG(acid) of 8.9 kcal/mol. Although there is a marked difference between the theoretical and experimental values of DeltaDeltaG(acid), both values point to unusually low gas-phase acidity for 1 relative to its diastereomer.