Nitric oxide (^˙NO) plays a central role in the pathogenesis of diverse inflammatory and infectious disorders,. The toxicity of ^˙NO is thought to be engendered, in part, by its reaction with superoxide (O˙⁻₂), yielding the potent oxidant peroxynitrite (ONOO⁻). However, evidence for a role of ONOO⁻in vivo is based largely upon detection of 3-nitrotyrosine in injured tissues^,,,,. We have recently demonstrated that nitrite (NO₂⁻), a major end-product of ^˙NO metabolism, readily promotes tyrosine nitration through formation of nitryl chloride (NO₂Cl) and nitrogen dioxide (^˙NO₂) by reaction with the inflammatory mediators hypochlorous acid (HOCl) or myeloperoxidase,. We now show that activated human polymorphonuclear neutrophils convert NO₂⁻ into NO₂Cl and ^˙NO₂ through myeloperoxidase-dependent pathways. Polymorphonuclear neutrophil-mediated nitration and chlorination of tyrosine residues or 4-hydroxyphenylacetic acid is enhanced by addition of NO₂⁻ or by fluxes of ^˙NO. Addition of ¹⁵NO₂⁻ led to ¹⁵N enrichment of nitrated phenolic substrates, confirming its role in polymorphonuclear neutrophil-mediated nitration reactions. Polymorphonuclear neutrophil-mediated inactivation of endothelial cell angiotensin-converting enzyme was exacerbated by NO₂⁻, illustrating the physiological significance of these reaction pathways to cellular dysfunction. Our data reveal that NO₂⁻ may regulate inflammatory processes through oxidative mechanisms, perhaps by contributing to the tyrosine nitration and chlorination observed in vivo.