Numerous disease states are associated with hemolysis or hemorrhage. Because red cells in the extravascular space tend to lyse quickly, hemoglobin (Hb) is released and is prone to autoxidation producing MetHb. Inorganic and organic peroxides may convert Hb and MetHb to higher oxidation states such as ferrylHb. FerrylHb is not a single chemical entity but is a mixture of globin- and porphyrin-centered radicals and covalently cross-linked Hb multimers. Oxidized Hb species are potent prooxidants caused mainly by heme release from oxidized Hb. Moreover, ferrylHb is a strong proinflammatory agonist that targets vascular endothelial cells. This proinflammatory effect of ferrylHb requires actin polymerization, is characterized by the upregulation of proinflammatory adhesion molecules, and is independent of heme release. Deleterious effects of native Hb are controlled by haptoglobin (Hp) that binds cell-free Hb avidly and facilitates its removal from circulation through the CD163 macrophage scavenger receptor-mediated endocytosis. Under circumstances of Hb oxidation, Hp can prevent heme release from MetHb, but unfortunately the Hp-mediated removal of Hb is severely compromised when Hb is structurally altered such as in ferrylHb allowing deleterious downstream reactions to occur even in the presence of Hp.