Neutrophil extracellular traps (NETs) consist of spindles of DNA together with histones and granule proteins including myeloperoxidase (MPO). They are released from neutrophils as an innate immune defense, but are increasingly implicated in thrombosis and the development of atherosclerosis and other chronic inflammatory pathologies. MPO present on the NETs produces the potent oxidant hypochlorous acid (HOCl), which reacts rapidly with proteins. In this study, we investigated the reactivity of HOCl with histones, which are the most abundant protein in the NETs, and assessed whether these modifications altered the effects of histones on vascular cell models. Experiments were performed with a preparation of histones containing histone H1, H2A, H2B, H3 and H4. Treatment of this histone preparation with reagent HOCl or the MPO/H2O2/Cl- system, resulted in the modification of Lys residues and the formation of unstable chloramines, which decomposed over 24 h. Evidence was also obtained for a dose- and time-dependent decrease in the concentration of Arg and Tyr residues, which was accompanied by the formation of stable oxidation products, including 3-chloro-Tyr and protein carbonyls. Exposure of human coronary artery endothelial cells (HCAEC) or human coronary artery smooth muscle cells (HCASMC) to non-modified histones resulted in a dose-dependent loss of viability, consistent with the known toxicity of histones when present in the extracellular environment. However, this loss in viability was attenuated on pre-treatment of the histones with HOCl. The ability of HOCl to decrease histone-induced cell death was dependent on the extent of oxidative protein modification. Given the close association of MPO with histones in NETs, these data provide new insight into potential pathways by which NETs could influence cellular function during chronic inflammation. This may be particularly relevant in atherosclerosis, where NETs are associated with lesion development and vascular dysfunction