OBJECTIVES: To investigate the effects of recombinant human erythropoietin on brain oxygenation in a model of diffuse traumatic brain injury. DESIGN: Adult male Wistar rats. SETTING: Neurosciences and physiology laboratories. INTERVENTIONS: Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were intravenously administered with either a saline solution or a recombinant human erythropoietin (5000 IU/kg). A third group received no traumatic brain injury insult (sham-operated). MEASUREMENTS AND MAIN RESULTS: Three series of experiments were conducted 2 hours after traumatic brain injury to investigate: 1) the effect of recombinant human erythropoietin on brain edema using diffusion-weighted magnetic resonance imaging and measurements of apparent diffusion coefficient (n = 11 rats per group); local brain oxygen saturation, mean transit time, and blood volume fraction were subsequently measured using a multiparametric magnetic resonance-based approach to estimate brain oxygenation and brain perfusion in the neocortex and caudoputamen; 2) the effect of recombinant human erythropoietin on brain tissue PO₂ in similar experiments (n = 5 rats per group); and 3) the cortical ultrastructural changes after treatment (n = 1 rat per group). Compared with the sham-operated group, traumatic brain injury saline rats showed a significant decrease in local brain oxygen saturation and in brain tissue PO₂ alongside brain edema formation and microvascular lumen collapse at H2. Treatment with recombinant human erythropoietin reversed all of these traumatic brain injury-induced changes. Brain perfusion (mean transit time and blood volume fraction) was comparable between the three groups of animals. CONCLUSION: Our findings indicate that brain hypoxia can be related to microcirculatory derangements and cell edema without evidence of brain ischemia. These changes were reversed with post-traumatic administration of recombinant human erythropoietin, thus offering new perspectives in the use of this drug in brain injury.