ABSTRACT: Background:Tidal hyperinflation can still occur with mechanical ventilation using low tidal volume (LVT) (6?mL/kg predicted body weight (PBW)) in acute respiratory distress syndrome (ARDS), despite a well-demonstrated reduction in mortality. Methods:Retrospective chart review from August 2012 to October 2014. Inclusion: Age >18years, PaO2/FiO2<200 with bilateral pulmonary infiltrates, absent heart failure, and ultra-protective mechanical ventilation (UPMV) defined as tidal volume (VT) <6?mL/kg PBW. Exclusion: UPMV use for <24?h. Demographics, admission Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, arterial blood gas, serum bicarbonate, ventilator parameters for pre-, during, and post-UPMV periods including modes, VT, peak inspiratory pressure (PIP), plateau pressure (Pplat), driving pressure, etc. were gathered. We compared lab and ventilator data for pre-, during, and post-UPMV periods. Results:Fifteen patients (male:female?=?7:8, age 42.13?±?11.29 years) satisfied criteria, APACHEII 20.6?±?7.1, mean days in intensive care unit and hospitalization were 18.5?±?8.85 and 20.81?±?9.78 days, 9 (60%) received paralysis and 7 (46.67%) required inotropes. Eleven patients had echocardiogram, 7 (63.64%) demonstrated right ventricular volume or pressure overload. Eleven patients (73.33%) survived. During-UPMV, VT ranged 2-5?mL/kg PBW(3.99?±?0.73), the arterial partial pressure of carbon dioxide (PaCO2) was higher than pre-UPMV values (84.81?±?18.95 cmH2O vs. 69.16?±?33.09 cmH2O), but pH was comparable and none received extracorporeal carbon dioxide removal (ECCO2-R). The positive end-expiratory pressure (14.18?±?7.56 vs. 12.31?±?6.84 cmH2O), PIP (38.21?±?12.89 vs. 32.59?±?9.88), and mean airway pressures (19.98?±?7.61 vs. 17.48?±?6.7?cm H2O) were higher during UPMV, but Pplat and PaO2/FiO2 were comparable during- and pre-UPMV. Driving pressure was observed to be higher in those who died than who survived (24.18?±?12.36 vs. 13.42?±?3.25). Conclusion:UPMV alone may be a safe alternative option for ARDS patients in centers without ECCO2-R.