The present study examined if free radicals and associated inflammatory sequelae influenced metabolic biomarkers involved in the neuro-endocrinological regulation of energy homoeostasis at high altitude. Sixteen mountaineers (11 males/five females) were matched for physical fitness and caloric intake and assigned in a double-blind manner to either antioxidant (n=8) or placebo (n=8) supplementation, which was enforced for 7 days at sea level and during an 11-day ascent to 4780 m. Enteral prophylaxis incorporated a daily bolus dose of 1 g of L-ascorbate, 400 international units of D,L-alpha-tocopherol acetate and 600 mg of alpha-lipoic acid. EPR (electron paramagnetic resonance) spectroscopic detection of PBN (alpha-phenyl-tert-butylnitrone) adducts confirmed an increase in the venous concentration of carbon-centred radicals at high altitude in the placebo group, whereas a decrease was observed in the antioxidant group (P<0.05 compared with that at sea level). EPR detection of DMSO/A*- (DMSO-supplemented ascorbate free radical) demonstrated that the increase in carbon-centred radicals at high altitude was associated with a decrease in ascorbate (r2=0.63; P<0.05). Ascent to high altitude (pooled placebo+antioxidant groups) also increased the expression of pro-inflammatory cytokines (P<0.05 compared with that at sea level) and biomarkers of skeletal tissue damage (P<0.05). Despite a general decrease in leptin, insulin and glucose at high altitude (pooled placebo+antioxidant groups; P<0.05 compared with that at sea level), persistent anorexia resulted in a selective loss of body fat (P<0.05). In conclusion, antioxidant prophylaxis decreased the concentration of carbon-centred radicals at high altitude (P<0.05 compared with the placebo group), but did not influence markers of inflammation, appetite-related peptides, ad libitum nutrient intake or body composition. Thus free radicals do not appear to be involved in the inflammatory response and subsequent control of eating behaviour at high altitude.