Oxidative DNA damage is decreased by the presence of O2 during Fe(2+)-mediated Fenton reactions when H2O2 is in excess. During these reactions, the presence of DNA increases H2O2 consumption relative to Fe2+ consumption under anaerobic conditions, but decreases H2O2 consumption relative to Fe2+ consumption under aerobic conditions. The pseudobimolecular rate constant of H2O2 consumption is the same under both conditions, however, indicating that the presence of DNA affects the oxidation and/or reduction of the iron pool. To understand the basis of these effects, DNA was replaced with ethanol as a model compound. Computer simulations of Fe2+ and H2O2 consumption were experimentally verified and allowed identification of the predominant reactions leading to the changes in stoichiometry. Based upon these results and upon qualitative and quantitative differences in DNA damages between aerobic and anaerobic conditions, it was concluded that, in the presence of DNA, Fe3+ is reduced by some DNA radicals. However, if O2 is present, these radicals react instead with O2 and the product of these reactions can then oxidize Fe2+. Mechanisms proposed for the alteration by O2 of products from dC- and dG-containing substrates after exposure to Fe and H2O2 fit these general schemes. These results provide another distinction between DNA damage caused by ionizing radiation and that caused by Fenton reactions.