The purpose of the present investigation was to determine the independent effects of hypoxia and physical exercise on peripheral cholecystokinin (CCK) metabolism in humans. Thirty-two physically active men were randomly assigned in a double-blind manner to either a normoxic (N; n = 14) or hypoxic (H; n = 18) group. During the acute study, subjects in the H group only participated in two tests, separated by 48 h, which involved a cycling test to exhaustion in normobaric normoxia and normobaric hypoxia (inspired O₂ fraction = 0.21 and 0.16, respectively). In the intermittent study, N and H groups cycle-trained for 4 wk at the same relative exercise intensity in both normoxia and hypoxia. Acute normoxic exercise consistently raised plasma CCK during both studies by 290-723%, which correlated with increases in the plasma ratio of free tryptophan to branched chain amino acids (r = 0.58-0.71, P < 0.05). In contrast, acute hypoxic exercise decreased CCK by 7.0 ± 5.5 pmol/l, which correlated with the decrease in arterial oxygen saturation (r = 0.56, P < 0.05). In the intermittent study, plasma CCK response at rest and after normoxic exercise was not altered after physical training, despite a slight decrease in adiposity. We conclude that peripheral CCK metabolism 1) is more sensitive to acute changes than chronic changes in energy expenditure and 2) is potentially associated with acute changes in tissue PO₂ and metabolic precursors of cerebral serotoninergic activity.