The reaction mechanism of the GPx-like oxidation of PhSH with H2O2 catalyzed by selenoxides proceeds via formation of the hydroxy perhydroxy selenane, which is a stronger oxidizing agent than selenoxide. A hydroxy perhydroxy selenane intermediate was observed by electrospray ionization mass spectrometry and Se-77 NMR spectroscopy in reactions of selenoxide 8 with H2O2. The initial velocity of oxidation of PhSH by H2O2 with selenoxide 8 is 4 orders of magnitude higher than that of 8 without peroxide. Selenoxide 8 is not reduced to selenide 6 by PhSH in the presence of H2O2. While electronic substituent effects have minimal impact on the catalytic performance of selenoxides, chelating groups increase the rate of catalysis.