The aim of this study was to address the effect of endurance training on tissue sensitivity to glucocorticoids (GC) in both resting and exercising conditions. In vitro dexamethasone inhibition of LPS-induced interleukin-6 secretion in cultures of peripheral monocytes was compared in untrained subjects (UT) and in endurance-trained men (ET) at the end of a 2-h run and during exercise recovery. We demonstrated an in vitro plasticity of sensitivity of monocytes to GC in ET men, superimposed to changes in systemic cortisol concentrations (plasma and saliva). Compared with sedentary men, similar resting cortisol levels in ET men are associated with decreased sensitivity of monocytes to GC 8 and 24 h after the end of the last training session (P < 0.05, ET vs. UT). Moreover, in these ET subjects, an acute bout of exercise increased the sensitivity of monocytes to GC (at 1000 and 1200; ET vs. UT, P > 0.05). This acute exercise-induced increase in tissue sensitivity to GC, which is synchronous with activation of the hypothalamo-pituitary adrenal axis, may act to shut off muscle inflammatory reaction and cytokine synthesis and then decrease exercise-induced muscle damage or inflammatory response. By contrast, the decreased sensitivity of monocytes to GC reported in ET men 24 h after the last bout of exercise may be related to the process of desensitization that may act to protect the body from prolonged, exercise-induced cortisol secretion. These acute and chronic effects of exercise on tissue sensitivity to GC demonstrate an adaptation of the hypothalamo-pituitary adrenal axis to repeated and prolonged exercise-induced increases in GC secretion.