Invasive mechanical ventilation is often initiated in the Emergency Department (ED), and mechanically ventilated patients may be kept in the ED for hours prior to intensive care unit (ICU) transfer. Although lung-protective ventilation is beneficial, particularly in acute respiratory distress syndrome (ARDS), it remains uncertain how often lung-protective tidal volumes are used in the ED, and whether lung-protective ventilation in this setting impacts patient outcomes.What is the association between the use of lung-protective ventilation in the ED and outcomes among invasively ventilated patients?Retrospective analysis (2011-2017) of a prospective registry from eight EDs enrolling consecutive adult patients (≥ 18 years) who received invasive mechanical ventilation in the ED. Lung-protective ventilation was defined by use of tidal volumes ≤ 8 mL/kg predicted body weight. The primary outcome was hospital mortality. Secondary outcomes included development of ARDS, hospital length of stay, and total hospital costs.We included 4,174 patients, of whom 2,437 (58.4%) received lung-protective ventilation in the ED. Use of lung-protective ventilation was associated with decreased odds of hospital death (adjusted odds ratio [aOR]: 0.91 [95% confidence interval [CI]: 0.84-0.96) and development of ARDS (aOR 0.87 [95% CI: 0.81-0.92]). Patients who received lung-protective ventilation in the ED had shorter median duration of mechanical ventilation (4 vs. 5 days, P < 0.01), shorter median hospital length of stay (11 vs. 14 days, P < 0.001), and reduced total hospital costs ($44,348 vs. $52,484, P = 0.03) compared to patients who received higher tidal volumes.Use of lung-protective ventilation in the ED was associated with important patient- and system-centered outcomes, including lower hospital mortality, decreased incidence of ARDS, lower hospital length of stay, and decreased total costs. Protocol development promoting the regular use of lung-protective ventilation in the ED may be of value.