Oxidatively generated damage to DNA has been implicated as causing mutations that lead to aging and disease. The one-electron oxidation of normal DNA leads to formation of a nucleobase radical cation that hops through the DNA until it is trapped irreversibly, primarily by reaction at guanine. It has been observed that 5-methylcytosine (C_m) is a mutational “hot-spot”. However, C_m in a Watson–Crick base pair with G is not especially susceptible to oxidatively induced damage. Radical cation hopping is inhibited in duplexes that contain C–A or C–T mispairs, but no reaction is detected at cytosine. In contrast, we find that the one-electron oxidation of DNA that contains C_m–A or C_m–T mispairs results primarily in reaction at C_m even in the presence of GG steps. The reaction at C_m is attributed to proton coupled electron transfer, which provides a relatively low activation barrier path for reaction at 5-methylcytosine. This enhanced reactivity of C_m in mispairs may contribute to the formation of mutational hot spots at C_m.