Hypoxia is implicated in aging and neurodegenerative diseases. We posited that changes in gene expression induced by ambient hypoxia at altitude may be neuroprotective to natives of these regions. We studied 30 men. Twenty natives of Cerro de Pasco (CP), altitude 4,338 m were examined in CP; then transported within 6 h to Lima (150 m-sea level) and examined 1 h after arrival. They were assessed by a Chronic Mountain Sickness-score (CMS-sc) in CP, 10 were normal Andeans and 10 had chronic mountain sickness (CMS), a sudden inexplicable loss of adaptation to their native environment. RNA was extracted from venous blood white cells. The Andeans were compared to 10 normal US men living at 1500 m using RT-PCR. We focused on the cyto-neuro-protective genes, Ataxia telangiectasia mutated (ATM), heme-oxygenase-1 (HMOX 1), heat shock protein-70 (HSP-70), heat shock protein-90 (HSP-90), and the neuroprotective enzyme, nicotinamide mononucleotide adenylyl transferase 1 (Nnmat 1). CMS patients had significantly higher levels of gene expression (HMOX-1, HSP-70, ATM) than Andean controls in CP. HSP-90 and Nmnat 1, however, were higher in Andean controls in all locations. Significant reductions of all gene products, within an hour of arriving in normoxia in Lima, were found. In Andean controls, the gene products in Lima fell to levels approaching US controls. Correlation and regression methods showed men with high expression of all gene products had an average CMS-sc=19.8; those with low expression a normal score (9.4, P=0.02). ATM expression was related to age (P<0.001). The natural experiment that unfolds in the mountainous regions of the world provides opportunities to study neuroprotection in intact humans.