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Hypothalamic-pituitary-adrenal axis dysfunction may lead to the occurrence of critical illness-related corticosteroid insufficiency. Critical illness-related corticosteroid insufficiency can easily occur after traumatic brain injury, but few studies have examined this occurrence. A multicenter, prospective, cohort study was performed to evaluate the function of the hypothalamic-pituitary-adrenal axis and the inci-dence of critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury. One hundred and forty patients with acute traumatic brain injury were enrolled from the neurosurgical departments of three tertiary-level hospitals in China, and the critical illness-related corticosteroid insufficiency incidence, critical-illness-related corticosteroid insufficiency-related risk factors, complications, and 28-day mortality among these patients was recorded. Critical illness-related corticosteroid insufficiency was diagnosed in patients with plasma total cortisol levels less than 10 μg/dL (275.9 nM) on post-injury day 4 or when serum cortisol was insufficiently suppressed (less than 50％) during a dexamethasone suppression test on post-injury day 5. The results demonstrated that critical illness-re-lated corticosteroid insufficiency occurred during the sub-acute phase of traumatic brain injury in 5.6％ of patients with mild injury, 22.5％ of patients with moderate injury, and 52.2％ of patients with severe injury. Traumatic brain injury-induced critical illness-related cortico-steroid insufficiency was strongly correlated to injury severity during the sub-acute stage of traumatic brain injury. Traumatic brain injury patients with critical illness-related corticosteroid insufficiency frequently presented with hemorrhagic cerebral contusions, diffuse axonal injury, brain hiation, and hypotension. Differences in the incidence of hospital-acquired pneumonia, gastrointestinal bleeding, and 28-day mortality were observed between patients with and without critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury. Hypotension, brain-injury severity, and the types of traumatic brain injury were independent risk factors for traumatic brain injury-induced critical illness-related corticosteroid insufficiency. These findings indicate that critical illness-related corticosteroid insufficiency is common during the sub-acute phase of traumatic brain injury and is strongly associated with poor progno-sis. The dexamethasone suppression test is a practical assay for the evaluation of hypothalamic-pituitary-adrenal axis function and for the diagnosis of critical illness-related corticosteroid insufficiency in patients with traumatic brain injury, especially those with hypotension, hemorrhagic cerebral contusions, diffuse axonal injury, and brain hiation. Sub-acute infection of acute traumatic brain injury may be an important factor associated with the occurrence and development of critical illness-related corticosteroid insufficiency. This study protocol was approved by the Ethics Committee of General Hospital of Tianjin Medical University, China in December 2011 (approval No. 201189).