OBJECTIVES: Data suggest that low tidal volume ventilation (LTVV) initiated in the emergency department (ED) has a positive impact on outcome. This systematic review and meta-analysis quantify the impact of ED-based LTVV on outcomes and ventilator settings in the ED and ICU. DATA SOURCES: We systematically reviewed MEDLINE, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, references, conferences, and ClinicalTrials.gov. STUDY SELECTION: Randomized and nonrandomized studies of mechanically ventilated ED adults were eligible. DATA EXTRACTION: Two reviewers independently screened abstracts. The primary outcome was mortality. Secondary outcomes included ventilation duration, lengths of stay, and occurrence rate of acute respiratory distress syndrome (ARDS). We assessed impact of ED LTVV interventions on ED and ICU tidal volumes. DATA SYNTHESIS: The search identified 1,023 studies. Eleven studies (n = 12,912) provided outcome data and were meta-analyzed; 10 additional studies (n = 1,863) provided descriptive ED tidal volume data. Overall quality of evidence was low. Random effect meta-analytic models revealed that ED LTVV was associated with lower mortality (26.5%) versus non-LTVV (31.1%) (odds ratio, 0.80 [0.72-0.88]). ED LTVV was associated with shorter ICU (mean difference, -1.0; 95% CI, -1.7 to -0.3) and hospital (mean difference, -1.2; 95% CI, -2.3 to -0.1) lengths of stay, more ventilator-free days (mean difference, 1.4; 95% CI, 0.4-2.4), and lower occurrence rate (4.5% vs 8.3%) of ARDS (odds ratio, 0.57 [0.44-0.75]). ED LTVV interventions were associated with reductions in ED (-1.5-mL/kg predicted body weight [PBW] [-1.9 to -1.0]; p < 0.001) and ICU (-1.0-mL/kg PBW [-1.8 to -0.2]; p = 0.01) tidal volume. CONCLUSIONS: The use of LTVV in the ED is associated with improved clinical outcomes and increased use of lung protection, recognizing low quality of evidence in this domain. Interventions aimed at implementing and sustaining LTVV in the ED should be explored.