Background/Aims: The diagnostic criteria for critical illness-related corticoid insufficiency (CIRCI) are not well established, particularly for children. In addition to alterations in adrenal function, cellular resistance to glucocorticoid action could contribute to CIRCI due to alterations in the functioning of the intracellular receptor protein for corticosteroids, the glucocorticoid receptor (GR). Methods: We have therefore undertaken a pilot, prospective study to assess whether cellular GR activity can be measured in peripheral blood mononuclear cells (PBMCs) from critically ill children. Results: Total and cytoplasmic, but not nuclear GR levels were significantly lower in PBMCs from critically ill children (i.e. sepsis/septic shock and traumatic brain injury) compared to healthy controls. While total cortisol concentrations did not differ between test groups, salivary and serum-free cortisol concentrations were significantly greater in both groups of children with critical illness. Cortisol-binding globulin levels were significantly lower in patients with sepsis/septic shock. Conclusions: The lower total and cytoplasmic receptor levels in critically ill children suggest that the GR-mediated response to exogenous glucocorticoid therapy may be limited. However, the nuclear transport of GR in critically ill patients suggests that residual receptors in these patients retain functionality and may be accessible to therapeutic treatments that maximize their activity.