The heme(a3)/Cu-B active site of cytochrome c oxidase is responsible for cellular nitrite reduction to nitric oxide; the same center can return NO to the nitrite pool via oxidative chemistry Here, we show that a partially reduced heme/Cu assembly reduces NO2- ion, producing nitric oxide. The heme serves as the reductant, but the Cu-II ion is also required. In turn, a mu-oxo heme-Fe-III-O-Cu-II complex facilitates NO oxidation to nitrite; the final products are the reduced heme and Cu-II-nitrito complexes.