This research provides novel insights into the underlying mechanism whereby the cyto- and neuro-protective heme binding protein hemopexin can be inactivated by reactive nitrogen species generated during the heme- and cytokine- driven inflammation that accompanies hemolysis. Nitration of amino acids is generally considered a selective and specific effect reflecting biological events. As we describe in a summary in the next paragraph, three tyrosine resides are preferentially targeted that reside in the heme binding site of apo-hemopexin. Hemopexin deficiency states develop in clinical sepsis and such modifications of hemopexin that we have identified and describe could also provide evidence-based guidance to physicians when heme toxicity is driving pathology to assess the timing and extent of hemopexin replenishment therapies and the patient responses to such treatment.