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There is much evidence that prolonged intense exercise suppresses the immune system. However, the intracellular biochemical mechanisms linking exercise and immunosuppression remain obscure. The purpose of this study was to investigate the hypothesis that exercise-induced inactivation of 5′AMP-activated protein kinase (AMPK) disrupts individual immune cell function, and thus may be linked to exercise-induced immunosuppression. To confirm AMPK’s role in immune cells, AMPK activity was assessed in cultured monocytic Mono Mac 6 (MM6) cells. The effects of single bouts of intense exercise (45 min cycling; 70% VO2 max) on several immune parameters including mononuclear cell AMPK phosphorylation were investigated in 10 male volunteers. In vitro, the mitochondrial ATP synthase inhibitor oligomycin brought about transient decreases in cellular [ATP] (0.41 ± 0.04 pmol/cell to 0.31 ± 0.02 pmol/cell), and activation of AMPKα1 (170.7% ± 31.2% basal) and the glycolytic enzyme inducible phosphofructokinase 2 (iPFK-2) (225.0% ± 46.1% basal), with the latter effects coinciding with recovery from ATP depletion. In contrast, exercise-induced transient (~1 h) decreases in AMPKα1 phosphorylation (64.4% ± 17.6% basal). This AMPK inactivation coincided with comparable transient decreases in other immune parameters (salivary IgA levels, serum cytokine levels, monocyte CD36 expression). Although the brief exercise bout employed here is not sufficient to cause full-fledged immunosuppression, exercise-induced transient decreases in mononuclear cell AMPK activation (as seen in this study) may cause energy depletion within individual immune cells, and therefore have an impact upon their ability to carry out their functions. Thus, we suggest that prolonged, repeated, high-intensity exercise that leads to clinically relevant immunosuppression may do so via AMPK inactivation within immune cells.