A series of water-soluble Ni(salen) complexes have been synthesized and studied under oxidative conditions with DNA. Experiments involving gel electrophoretic analysis, substituent effect studies, and mass spectral characterization point to the formation of covalent adducts of the salen ligand with guanine nucleobases. The mechanism of this novel reactivity of transition metal complexes with nucleic acids is discussed in comparison with nickel(II) complexes of peptides and other ligands.