Bisperoxovanadium(V) compounds with bidentate ligands have shown tumor growth inhibition by cleaving DNA. The kinetics and mechanisms of ligand substitution reactions of two bisperoxovanadium(V) compounds [VO(O-2)(2)(bpy)](bpVbpy) and [VO(O-2)(2)(phen)](-)(bpVphen) with entering ligands picolinic acid (pic) and dipicolinic acid (dipic) at physiological pH are reported, and its relevance to their DNA-cleavage activities are discussed. The products of the ligand substitution reactions with pic and dipic are the monoperoxo complexes [VO(O-2)(pic)(2)](-) and [VO(O-2)(dipic)(H2O)](-), respectively. V-51 NMR experiments indicate that bpVphen is substantially more inert in aqueous solution than bpVbpy. As a result, bpVbpy is more prone to ligand substitution and subsequent conversion to monoperoxo species. The rate of reaction for bpVbpy was faster than that of bpVphen by an order of magnitude, indicating that the ancillary ligand plays an important role in ligand substitution reactions. The ligand substitution reactions of bpVbpy feature first-order dependence on both [pic](T) and [dipic](T) whereas the substitution kinetics of bpVphen feature saturation behavior with dipic. The substitution reactions of both bpVbpy and bpVphen with pic showed first-order dependence on [H+] whereas no acid dependence was observed for the reactions with dipic. Hydrogen peroxide was determined to be a competitive inhibitor with respect to dipic. The ligand substitution reaction mechanisms and the rate laws consistent with these results are presented. The substitution reactions with pic and dipic proceed through different mechanisms; the substitution reactions with dipic proceed via solvolysis as the first step in the mechanisms whereas the reactions with pic bypass solvolysis to go through a mixed ligand monoperoxo vanadium intermediate.