Like other humans exposed to extreme trauma, patients who have been treated in an intensive care unit (ICU) often report traumatic memories. Extremely traumatic memories from the ICU in some of these patients are associated with the development of posttraumatic stress disorder (PTSD), which results in significant impairments in health-related quality of life (HRQL) outcomes of ICU therapy. Severely ill patients in the ICU often show insufficient endogenous glucocorticoid signaling, which has recently been termed critical illness-related corticosteroid insufficiency (CIRCI). We performed several controlled trials in ICU patients with suspected CIRCI from septic shock or cardiac surgery, which indicated that the administration of glucocorticoids (stress doses of hydrocortisone) during ICU treatment results in a significant reduction of PTSD symptoms in long-term survivors as well as improvements in HRQL outcomes. Stress doses of hydrocortisone could help to surmount impaired glucocorticoid signaling from CIRCI during critical illness resulting in a downregulation of the stress response as well as inhibition of traumatic memory retrieval and facilitated extinction of aversive information.