Semiempirical AM1 and PM3 calculations were used to study the electron-transfer-catalyzed splitting of oxetanes and azetidines that have been proposed as intermediates in the photoenzymatic repair of the (6−4) photoproducts of dipyrimidine sites in DNA by (6−4) photolyase. The calculations show that the gas-phase splitting of an anion radical to a product complex is more exothermic than that of a cation radical, and that both are more exothermic than the neutral pathway. Low-energy pathways for splitting were found to occur by nonconcerted, two-step mechanisms for both anion and cation radical pathways, but only the anion radicals had lower rate-determining barriers for splitting than did the neutral species. In the anion radical pathway, which is thought to be followed by the enzymatic reaction, cleavage of the C5−O4‘ or C5−N4‘ bond followed by cleavage of the C6−C4‘ bond is more favorable kinetically than cleavage in the reverse order. Though the barrier for cleaving the C5−N4‘ bond first is significantly higher for the radical anion of the azetidine than that for cleaving the C5−O4‘ bond of the oxetane, protonation of the azetidine nitrogen of the radical anion leads to spontaneous cleavage of the C5−N4‘ bond. In the cation radical pathway, cleavage of the C6−C4‘ bond followed by cleavage of the C5−O4‘ or the C5−N4‘ bond is more favorable kinetically than cleavage in the reverse order. We also found that the Dewar valence isomer can be reversed to the (6−4) product by both radical anion and radical cation pathways, though the anionic pathway has a much lower barrier. These calculations are in accord with the observation that the Dewar valence isomer is also reversed to the parent nucleotides by (6−4) photolyase, though much less efficiently than the (6−4) products.