Base-catalyzed H/D-exchange for α- and β-isophorone (1 and 2, resp.) was monitored by NMR spectroscopy to identify the number and nature of reactive sites. Results show that α-isophorone (1) undergoes H/D exchange at up to four different sites depending on reaction conditions. β-Isophorone (2), on the other hand, exhibits activity at two sites, predominantly at the α-position, under comparable conditions. Quantum-chemical calculations indicate that the thermodynamically more-stable anions formed upon proton abstraction from isophorone are not favored kinetically in all cases. Thermodynamically unfavorable H/D-exchange at the α-position in 1, which is observed experimentally, is explained via intermediate formation of γ-isophorone (3) with subsequent conjugation to the α-isomer. Differences observed in the reactivities of the two isomers and differences in reactivity of 1 under various conditions in reactions involving proton abstraction as an initial step may be partly explained on the basis of these results.