Aim: The aim of this study was to examine if erythropoietin (EPO) has the potential to act as a biological antioxidant and determine the underlying mechanisms. Methods: The rate at which its recombinant form (rHuEPO) reacts with hydroxyl (HO˙), 2,2-diphenyl-1-picrylhydrazyl (DPPH˙) and peroxyl (ROO˙) radicals was evaluated in-vitro. The relationship between the erythopoietic and oxidative–nitrosative stress response to poikilocapneic hypoxia was determined separately in-vivo by sampling arterial blood from eleven males in normoxia and following 12 h exposure to 13% oxygen. Electron paramagnetic resonance spectroscopy, ELISA and ozone-based chemiluminescence were employed for direct detection of ascorbate (A˙) and N-tert-butyl-alpha-phenylnitrone spin-trapped alkyl (PBN-OR) radicals, 3-nitrotyrosine (3-NT) and nitrite (NO2 ). Results: We found rHuEPO to be a potent scavenger of HO˙ (kr = 1.03–1.66 x 10e11 M-1.s-1) with the capacity to inhibit Fenton chemistry through catalytic iron chelation. Its ability to scavenge DPPH˙ and ROO˙ was also superior compared to other more conventional antioxidants. Hypoxia was associated with a rise in arterial EPO and free radical-mediated reduction in nitric oxide, indicative of oxidative–nitrosative stress. The latter was confirmed by an increased systemic formation of A˙, PBN-OR, 3-NT and corresponding loss of NO2 (P