The reaction of the anticancer compound (eta(6)-benzene)Ru(en)(OH2) (1) toward the nucleobases guanine, adenine, and cytosine is studied computationally using DFT/BP86 calculations. The aqua leaving group of such compounds is known to undergo ligand exchange reactions with nucleophilic centers in DNA and preferentially with the N7 atom of guanine, N7(G). Our results show that an H-bonded reactant adduct with nucleobases is formed via either the aqua ligand (cis adduct) or the en (ethylenediamine) ligand (trans adduct) of 1. All studied nucleobases favor an H-bonded cis adduct. Only guanine forms also a trans reactant adduct in the gas phase. The guanine N7 and O6 atoms in this trans adduct are situated in an ideal position to form each a strong H-bond to both amino groups of the en ligand of 1. A docking study shows that this unique recognition pattern is also plausible for the interaction with double stranded DNA. For the reaction of 1 with guanine, we identified three different reaction pathways: (i) A cis (G)N7-Ru-OH2 transition state (TS). (ii) A direct trans reaction pathway. (iii) A 2-step trans mechanism. The activation energies for the cis pathway are smaller than for the trans pathways. The ultimately formed Ru-N7(G) product is characterized by a thermally stable H-bond between the O6(G) and a diamine-NH2 hydrogen.