Background and Aims: Erythropoietin (EPO) is the key regulator of erythropoiesis, promoting the survival, proliferation and differentiation of erythrocytic progenitors to increase red blood cell mass for the maintenance of systemic O2 homeostasis (Jelkmann, 2011). However, its action is not merely constrained to that of an endocrine hormone and broader interest in EPO as a cytoprotective molecule has evolved over recent years (Brines and Cerami, 2012). Emerging evidence suggests that the recombinant form of human erythropoietin (rHuEPO) may function directly as an antioxidant though the underlying mechanisms remain unclear (Katavetin et al., 2007). The present study employed an integrated approach to determine if EPO does indeed have the molecular potential to act as a biological antioxidant with a specific focus on its ability to suppress hydroxyl radical (HO●) formation. Methods: In-vivo study: Radial arterial blood was obtained from 11 healthy males aged 27 ± 4 y old in normoxia (21% O2) and following 12 h passive exposure to hypoxia (~13% O2). Blood was assayed for EPO using high-sensitivity ELISA. Electron paramagnetic resonance spectroscopy was employed for the direct detection of ascorbate (A●-) and spin-trapped (N-tert-butyl-α-phenylnitrone) lipid-derived oxygen-centred alkoxyl (PBN-OR) radicals as an index of free radical-mediated lipid peroxidation (Bailey et al., 2011). In-vitro study: The second-order rate constant for the reaction of rHuEPO with HO● (krHuEPO) generated by Fenton chemistry was determined via the deoxyribose (DR) method (Halliwell et al., 1987). Following confirmation of distribution normality using Shapiro-Wilk W tests, data were analysed using paired samples t-tests and relationships determined with Pearson Product Moment Correlations. All data are expressed as mean ± standard deviation (SD). Results: In-vivo study: Hypoxia was associated with an increase in EPO (6.2 ± 2.0 to 22.1 ± 6.3 mU.mL-1, P < 0.05) that correlated against the elevation in A●- [2,384 ± 166 to 3,087 ± 276 arbitrary units (AU), P < 0.05] and PBN-OR (16,321 ± 2,488 to 19,076 ± 2,122 AU, P < 0.05) as illustrated in Figure 1 A-B. In-vitro study: krHuEPO was shown to be diffusion-controlled at 1.66 × 1011 M-1.s-1 (Figure 2). The site-specific plot suggests that rHuEPO was able to inhibit iron ion-dependant DR degradation and thus capable of binding ions into chelates with poor ability to form HO●. Conclusions: Collectively, these findings suggest that the cytoprotective benefits of rHuEPO may be due to its exceptional ability to suppress HO● formation subsequent to catalytic iron chelation. In addition to its traditionally accepted haematopoietic role, the systemic rise in EPO during hypoxia may also serve to counter oxidative stress.