The role of NO and nitrite-bound methemoglobin (Hb(III)NO(2)(-)) in hypoxic signaling is highly controversial. One provoking possibility is that hemoglobin (Hb) functions as a nitrite anhydrase, producing N2O3 (from nitrite) as an NO carrier. The ability of Hb to generate N2O3 would provide an intriguing means of NO release from red blood cells. We have investigated this proposed new reactivity of Hb using density functional theory (DFT) calculations. For this purpose, models of the Hb/myoglobin (Mb) active site have been constructed. Our results show that the O-bound (nitrito) form of Hb/Mb(III)NO(2)(-) is essential for the formation of N2O3. The formation and release of N2O3 is shown to be energetically favorable by 1-3 kcal/mol, indicating that the anhydrase function of Hb/Mb is biologically feasible.