Naturally occurring intrastrand oxidative crosslink lesions have proven to be a potent source of endogenous DNA damage. Among the variety of lesions that can be formed and have been identified, G[8-5]C damage (in which the C8 atom of a guanine is covalently bonded to the CS atom of a nearby cytosine belonging to the same strand) occurs with a low incidence yet takes on special importance because of its high mutagenicity. Hybrid Car-Parrinello molecular dynamics simulations, rooted in density functional theory and coupled to molecular mechanics, have been performed to shed light on the cyclization process. The activation free energy of the reacting subsystem embedded in a solvated dodecamer is estimated to be similar to 12.4 kcal/mol, which is similar to 3 kcal/mol higher than the value for the prototypical G[8-5m]T lesion inferred employing the same theoretical framework [Garrec, 3., Patel, C., Rothlisberger, U., and Dumont, E. (2012) J. Am. Chem. Soc. 134, 2111-2119]. This study also situates the G[8-5m]mC lesion at an intermediate activation free energy (similar to 10.5 kcal/mol). The order of reactivity in DNA (T-center dot > mC(center dot) > C-center dot) is reversed compared to that in the reacting subsystems in the gas phase (C-center dot > mC(center dot) > T-center dot), stressing the crucial role of the solvated B-helix environment. The results of our simulations also characterize a more severe distortion for G[8-5]C than for methylene-bridged intrastrand cross-links.