Introduction: Non-neurological complications in patients with severe traumatic brain injury (TBI) are frequent, worsening the prognosis, but the pathophysiology of systemic complications after TBI is unclear. The purpose of this study was to analyze non-neurological complications in patients with severe TBI admitted to the ICU, the impact of these complications on mortality, and their possible correlation with TBI severity. Methods: An observational retrospective cohort study was conducted in one multidisciplinary ICU of a university hospital (35 beds); 224 consecutive adult patients with severe TBI (initial Glasgow Coma Scale (GCS) < 9) admitted to the ICU were included. Neurological and non-neurological variables were recorded. Results: Sepsis occurred in 75% of patients, respiratory infections in 68%, hypotension in 44%, severe respiratory failure (arterial oxygen pressure/oxygen inspired fraction ratio (PaO2/FiO(2)) < 200) in 41% and acute kidney injury (AKI) in 8%. The multivariate analysis showed that Glasgow Outcome Score (GOS) at one year was independently associated with age, initial GCS 3 to 5, worst Traumatic Coma Data Bank (TCDB) first computed tomography (CT) scan and the presence of intracranial hypertension but not AKI. Hospital mortality was independently associated with initial GSC 3 to 5, worst TCDB first CT scan, the presence of intracranial hypertension and AKI. The presence of AKI regardless of GCS multiplied risk of death 6.17 times (95% confidence interval (CI): 1.37 to 27.78) (P < 0.02), while ICU hypotension increased the risk of death in patients with initial scores of 3 to 5 on the GCS 4.28 times (95% CI: 1.22 to15.07) (P < 0.05). Conclusions: Low initial GCS, worst first CT scan, intracranial hypertension and AKI determined hospital mortality in severe TBI patients. Besides the direct effect of low GCS on mortality, this neurological condition also is associated with ICU hypotension which increases hospital mortality among patients with severe TBI. These findings add to previous studies that showed that non-neurological complications increase the length of stay and morbidity in the ICU but do not increase mortality, with the exception of AKI and hypotension in low GCS (3 to 5).