The formation of covalent linkages between two vicinal nucleotides has been proved experimentally to constitute a particularly deleterious class of DNA lesions. These tandem lesions by essence present a competitive chemistry. The density functional theory with dispersion (DFT-D) method is shown to dramatically improve the theoretical description of the formation of a prototypical intrastrand cross-link, when compared to pure or hybrid GGA functionals which strongly deviate from the π–π self-stacking mode, as dinucleotides are artificially stabilized by the formation of unrealistic intramolecular hydrogen bonds (HBs). Inclusion of London dispersion correction restores a more realistic picture of the reactant structure and also of geometries and energies along the reaction profile. This paves the way toward a robust insilico screening of intrastrand cross-link DNA defects.