Oxidant generation during regular physical exercise training may influence the adaptive responses that have been shown to confer protection against oxidative stress induced by subsequent acute exercise. To examine this, we randomly assigned 32 males to either a normoxic (n=14) or a hypoxic (n=18) group. During the acute phase, subjects in the hypoxic group performed two maximal cycling tests in a randomized double-blind fashion: one under conditions of normoxia and the other under hypoxic conditions (inspired fraction of O(2)=0.21 and 0.16 respectively). During the intermittent phase, the normoxic and hypoxic groups each trained for 4 weeks at the same relative exercise intensity, under conditions of normoxia and hypoxia respectively. During acute exercise under hypoxic conditions, the venous concentrations of lipid hydroperoxides and malondialdehyde were increased, despite a comparatively lower maximal oxygen uptake (VO(2max)) (P<0.05 compared with normoxia). The increases in lipid hydroperoxides and malondialdehyde were correlated with the exercise-induced decrease in arterial haemoglobin oxygen saturation (r=-0.61 and r=-0.50 respectively; P<0.05), but not with VO(2max). Intermittent hypoxic training attenuated the increases in lipid hydroperoxides and malondialdehyde induced by acute normoxic exercise more effectively than did normoxic training, due to a selective mobilization of alpha-tocopherol (P<0.05). The latter was related to enhanced exercise-induced mobilization/oxidation of blood lipids due to a selective increase in VO(2max) (P<0.05 compared with normoxic group). We conclude that lipid peroxidation induced by acute exercise (1) increases during hypoxia; (2) is not regulated exclusively by a mass action effect of VO(2); and (3) is selectively attenuated by regular hypoxic training. Oxidative stress may thus be considered as a biological prerequisite for adaptation to physical stress in humans.