Theory is developed for th pH dependence of isotope effects in a mechanism where a pH-dependent step precedes the isotope-sensitive bond-breaking step, and the rate of the latter varies only slightly with the state of protonation of the acid-base catalytic group on the enzyme. In such a mechanism, the isotope effects fall to 1.0 in the forward direction and to the equilibrium isotope effect in the reverse direction at pH values where the pH-sensitive step becomes totally rate limiting in the reverse direction. This model accurately describes the kinetics of yeast alcohol dehydrogenase, where V/Kacetone and the isotope effects on V2-propanol and V/K2-propanol decrease above a pK of 8.8 (both isotope effects becoming 1.0 at pH 10). The model also fits the kinetics of liver alcohol dehydrogenase, where Vcyclohexanol and V/Kcyclohexanol decrease below pKs of 6.2 and 7.1, and above pKs of 9.5 and 10.3. pKi trifluoroethanol decreases below a pK of 7.2, and above pK of 10.1, while pKi isobutyramide drops above a pK of 10.0. Vcyclohexanone decreases above a pK of 8.4 while V/Kcyclohexanone decreases above pKs of 8.8 and 9.7. Isotope effects on V/Kcyclohexanol and V/Kcyclohexanone decrease above identical pKs of 9.4 to values of 1 and 0.88, respectively, at pH 11. Comparison of a value of 2.5 for D(V/Kcyclohexanol) with an average value of 5.53 for T(V/Kcyclohexanol) allowed circulation of 6.3 as the intrinsic deuterium isotope effect. These data suggest that E-DPN-alcohol undergoes a proton transfer to the enzyme to give an EH-DPN-alkoxide complex which can lose its proton at high pH to give E-DPN-alkoxide and that both of these alkoxide complexes undergo hydride transfer to give DPNH and ketone. the alkoxide intermediate is not free to dissociate until it is protonated, either because it is coordinated to Zn or because the enzyme is in a closed catalytic configuration.