The oxidative electrochemistry of trans-[Re(O)(2)(4-OMe-py)(4)](+) in the presence of DNA has been studied. The complex exhibits a reversible oxidation at E(1/2)(VI/V) = 1.00 V (vs Ag/AgCl) in buffer or in the presence of poly(dA).poly(dT). However, in the presence of calf thymus DNA or poly(dG).poly(dC), a dramatic catalytic enhancement is observed. An identical result is obtained with Fe(5-Cl-phen)(3)(2+) (E(1/2)(III/II) = 1.02 V), but no electrocatalytic enhancement is observed with trans-[Re(O)(2)(py)(2)(dmap)(2)](+) (E(1/2) = 0.90 V). Electrophoresis of plasmids electrolyzed at 1.2 V in the presence of trans- [Re(O)(2)(4-OMe-py)(4)](+) show relaxation from form I to form II, and analogous reactions with 5’-end P-32-labeled synthetic oligonucleotides show piperidine-labile cleavage specifically at guanine. The combined results point to an electrocatalytic mechanism where the oxidized metal complex oxidizes guanine in DNA by one electron via an efficient, outer-sphere mechanism. Moreover, the experiments demonstrate a potential for the one-electron oxidation of guanine in double-helical DNA at neutral pH of between 0.90 and 1.00 V. This result should provide insight into the mechanisms of DNA oxidation by chemical agents and by ionizing radiation.