Reaction of a single-stranded oligodeoxynucleotide or a 17-base hairpin-forming oligodeoxynucleotide with CoCl2 and KHSO5 produced guanine-specific cleavage after piperidine treatment. The observed reactivity is shown to be nearly twice that obtained for NiCR (CR=2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),2,11,13,15-pentaene) under equivalent conditions, although NiCR displays a slightly higher degree of selectivity for unpaired guanine residues. Cobalt-induced DNA modification was catalytic with respect to the,metal complex and was observed at temperatures up to 80 degrees C, conditions under which NiCR was ineffective. Mechanistic studies of the cobalt-mediated reaction suggest that SO4.- is responsible for guanine oxidation. Reaction with tRNA(Phe) induced aniline . HOAc-labile (pH 4.5) lesions also at accessible guanine sites. The high reactivities of G20 acid G34 are consistent with attack of SO4.- on the rr face of the guanine heterocycle as opposed to recognition of G N7 as proposed for NiCR. CoCl2 should become an extremely attractive probe of nucleic acid structure since it induces base-specific and conformation-specific cleavage of DNA under a much wider variety of experimental conditions than NiCR, acts with a different mode of guanine selectivity than do nickel complexes, and is commercially available.