Abstract only At high altitude, exercise‐induced arterial desaturation decreases regional cerebral oxygenation (rO 2 Hb). Erythropoietin (EPO) potentiates endothelium‐mediated dilation of isolated, perfused rat middle cerebral arteries. To determine if EPO administration in humans mitigated the decreased cerebral rO 2 Hb during exercise within the first 3 h at 4500 m eight healthy male lowlanders received a subcutaneous injection of either EPO (600 IU/Kg) or a placebo (PLA) (0.9% NaCl) ~12 hr prior to ascent in a hypobaric chamber in a double‐blind, cross‐over study. We measured frontal lobe rO 2 Hb by NIRS, arterial saturation (SaO 2 ) by pulse oximetry, and PetO 2 and PetCO 2 by metabolic cart during rest and 50 W cycling. At 4500 m, serum EPO levels were (mean ± SD) 6 ± 2 and 720 ± 273 mU/ml for PLA and EPO trials, respectively. From rest‐to‐ exercise SaO 2 decreased similarly in both trials (PLA: −6 ± 4 and EPO: −8 ± 4%), but rSO 2 declined less in EPO (PLA: −2.12 ± 1.93 and EPO: −1.47 ± 2.40 μM, p=0.027), while rest and exercise PetO 2 and PetCO 2 were similar for both trials. Conclusion since PO 2 and PCO 2 were constant and not likely changing cerebral vasomotor activity, the smaller exercise‐induced decline in rO 2 Hb following EPO administration supports the hypothesis that increasing circulating EPO potentiates dilation of cerebral blood vessels at high altitude. Funding: USAMRMC. Authors’ views; not official U.S. Army or DoD policy.