Complex formation between nitrosoglutathione (GSNO) and Zn(II), Cd(II), and Ni(II) ions was studied by potentiometry and spectroscopic techniques. GSNO forms simple ML and ML2 type complexes (L = GSNO) with these ions. The stability of GSNO in HEPES buffer solution, pH 7.4, increased in the presence of both Zn(II) and Cd(II), due to an indirect mechanism. A concentration-dependent destabilization of GSNO by Ni(II) ions was found to be linearly dependent on the NiL complex concentration. NiL forms ternary complexes readily. The NiLA- stoichiometry was found for l-His, and NiHLB3- and NiLB4- complexes were detected for GSSG as the second ligand. The formation of these complexes was found to inhibit GSNO decay, by limiting the concentration of the NiL complex. The mechanism of Ni(II)-assisted GSNO decomposition contains several steps, with a hypothetical ternary complex with GSH as a likely active form. These results provide experimental evidence for the stabilization of GSNO in solution by metal ions, which may provide an additional level of control and/or impairment of cellular redox signaling. The Ni(II)-dependent destabilization of GSNO may constitute a novel epigenetic mechanism in nickel carcinogenesis.