Erythropoietin (EPO) administration provides neuroprotection during severe hypoxia associated with stroke or surgery. PURPOSE: To test the hypothesis that increasing EPO levels in lowland residents prior to high altitude exposure will mitigate cognitive performance decrements and acute mountain sickness (AMS). METHODS: Twelve healthy fit men (mean ± SD: 21 ± 3 yr, 176 ± 7 cm, 83 ± 10 kg), residing at low altitude volunteered to participate in a placebo controlled, double-blinded cross-over study with the volunteers receiving a subcutaneous injection of either EPO (600 IU/Kg SC, PROCRIT®, Ortho Biotech) or a placebo (PLA) (saline, 0.9% NaCl) ∼12 hr prior to ascent to 4500m in a hypobaric chamber. After practice with test procedures, each participated in two, 3 day trials (day 1: sea level; days 2-3: 30 hr altitude exposure) with a 2 week recovery between the two trials. Cognitive performance was assessed by 6 tests of the Automated Neuropsychological Assessment Metrics (ANAM), and AMS was assessed using the Environmental Symptoms Questionnaire to calculate the AMS-Cerebral (AMS-C) factor score. AMS was diagnosed as an AMS-C score ≥0.7. Resting arterial oxygen saturation (SaO2), and heart rate (HR) were measured by pulse oximetry. RESULTS: At time of ascent to 4500 m, EPO levels were 6 ± 2 and 720 ± 273 mU/ml, respectively, for PLA and EPO trials. Over the 30-h altitude exposure resting SaO2 (PLA: 83 ± 10%, EPO: 84 ± 14%), and HR (PLA: 88 ± 14 bpm, EPO: 93 ± 17 bpm) did not differ significantly between trials. Performance on 5 of the ANAM tests was significantly decreased at 4500 m, and maximum decrements were similar in the PLA (7-25%) and EPO (6-18%) trials. The AMS incidence (100%), and peak symptom severity (PLA: 2.60 ± 0.97, and EPO: 2.32 ± 1.17) were similar in both trials. CONCLUSION: In the dosage given (600 U/kg), EPO did not mitigate cognitive performance deficits or AMS following rapid ascent to 4500 m. These results show that this EPO dosage and timing of administration did not elicit any functionally relevant neuroprotection. Funding: USAMRMC and USSOCOM. Authors' views; not official U.S. Army or DoD policy.