PURPOSE: Current mechanical ventilation practices for patients with acute brain injury (ABI) are poorly defined. This study aimed to describe ventilator settings/parameters used in intensive care units (ICUs) and evaluate their association with clinical outcomes in these patients. METHODS: An international, prospective, multicenter, observational study was conducted across 74 ICUs in 26 countries, including adult patients with ABI (e.g., traumatic brain injury, intracranial hemorrhage, subarachnoid hemorrhage, and acute ischemic stroke), who required ICU admission and invasive mechanical ventilation. Ventilatory settings were recorded daily during the first week and on days 10 and 14. ICU and 6-months mortality and 6-months neurological outcome were evaluated. RESULTS: On admission, 2095 recruited patients (median age 58 [interquartile range 45-70] years, 66.1% male) had a median plateau pressure (Pplat) of 15 (13-18) cmH CONCLUSIONS: Protective ventilation strategies are commonly used in ABI patients but with high variability across different countries. Ventilator settings during ICU stay were associated with an increased risk of ICU and 6-month mortality, but not an unfavorable neurological outcome.