Selenomethionine, an amino acid occurring in proteins in place of methionine, reacts efficiently with oxidants, e.g., peroxynitrite, a biological oxidant generated in inflammatory states, to produce the oxidation product, methionine selenoxide. The present work describes the rapid and efficient reduction of the selenoxide to selenomethionine by glutathione in a stoichiometric reaction utilizing two equivalents of thiol. This nonenzymatic reaction establishes a defense line against peroxynitrite or other oxidants by selenomethionine residues in proteins, maintained by the ubiquitous thiol, glutathione.