The aim of this study was to address the effect of endurance training on tissue sensitivity to glucocorticoids (GC), both in resting and exercising conditions. In vitro dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 secretion in cultures of peripheral monocytes was compared in untrained subjects (UT) and in endurance-trained men (ET) 24 h after the end of the last session of exercise. Moreover, to evaluate the effect of an exercise-induced increase in GC concentrations in ET men, sensitivity to GC was further studied at the end of a two-hour run and during exercise recovery. We demonstrate an in vitro plasticity of sensitivity of monocytes to GC in ET men, superimposed to changes in systemic cortisol concentrations (plasma and saliva). Compared to sedentary men, similar resting cortisol levels in ET men are associated with decreased sensitivity of monocytes to GC, 8 h 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 to the levels assayed in untrained men (1000 h and 1200 h, ET vs UT: p>0.05). This acute exercise-induced increase in tissue sensitivity to GC which is synchronous with activation of the HPA axis may act to shut off muscle inflammatory reaction 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 which may act to protect the body from prolonged exercise-induced cortisol secretion. In conclusion, the acute and chronic effects of exercise on tissue sensitivity to GC in ET men add important insight into the role of the adaptation of the HPA axis to repeated and prolonged exercise-induced increases in GC secretion.