Like superoxide dismutase (SOD), nitroxide stable radicals can catalyze the dismutation of superoxide radicals and provide protection against oxidative stress. The SOD-mimic activity of nitroxides prompted the study of their biological effects; however, accumulated evidence suggested that the reactions of nitroxide with redox-active transition metals play an important role in its antioxidative activity. The present study concentrated on the kinetics of the reaction of iron(II) coordinated to various ligands with piperidinyl and pyrrolidinyl nitroxides [nitroxide + H+ + Fe(II) (k-1)reversible arrow(k1) hydroxylamine + Fe(III)]. The effects of pH, temperature, buffer, and ligands on the reaction kinetics were examined. W-Vis absorption spectroscopy and electron paramagnetic resonance spectrometry were used to follow the change in the concentrations of iron and the nitroxide, respectively. The results show that under physiological conditions: (a) equilibrium 1 is shifted to the right; (b) OH-catalyzes the oxidation of iron and shifts the equilibrium further to the right; (c) phosphate, even at the submillimolar range, greatly catalyzes the reaction; and (d) piperidinyl nitroxides are more effective than pyrrolidinyl derivatives in oxidizing iron. The results imply that nitroxides rapidly and effectively oxidize iron, and most likely copper too, in the pool of chelatable redox-active metals in cells and tissues. This oxidation prevents the Fenton chemistry, suppresses the oxidative injury, and explains the narrow time-window antioxidative activity of nitroxides observed using cellular, animal, and organ experimental models.