Introduction: Higher dead space is associated with increased mortality and prolonged mechanical ventilation in children and adults with acute respiratory distress syndrome (ARDS). Dead space assessment typically requires measurement of PCO2. Ventilatory efficiency (minute ventilation/VCO2) may be a useful non-invasive continuous dead space surrogate with prognostic value. Methods: Prospective observational cohort study. Mechanically ventilated children with ARDS were monitored with volumetric capnography. The first simultaneous measurements of ventilatory efficiency, physiologic dead space (VD/VT=[PCO2-PeCO2]/PCO2), the end-tidal alveolar dead space fraction (AVDSf=[PCO2-PETCO2]/PCO2), and oxygenation index (OI) within the first 72h of mechanical ventilation were used in the analysis. Results: There were 80 enrolled children. Median VD/VT was 0.46 (IQR 0.38, 0.58) and OI was 7.5 (IQR 4.6, 14.2). Mortality was 19%. The correlation between VD/VT and ventilatory efficiency (rs=0.68, p< 0.001) and VD/VT and AVDSf (rs=0.74, p< 0.001) were high. The correlation between AVDSf and ventilatory efficiency was lower (rs=0.48, p< 0.001). After controlling for OI and severity of illness (PRISM III) in separate multivariable models, higher VD/VT (per 0.1 increase, OR 1.66 [95% CI 1.04, 2.64], p=0.035), ventilatory efficiency (per 0.01, OR 1.69 [95% CI 1.10, 2.59], p=0.017), and AVDSf (per 0.1, OR 1.88 (95% CI 1.05, 3.38), p=0.035) were all associated with increased mortality. However, VD/VT, ventilatory efficiency, and AVDSf were not independently associated with fewer 28-day ventilator free days (VFD) or longer length of mechanical ventilation in survivors (LMV) after controlling for OI and PRISM III. OI was not associated with mortality after controlling for any of the dead space terms (all p>0.15) and PRISM III, but was independently associated with fewer 28-day VFDs (all p< 0.03) and longer LMV (all p< 0.01). Conclusions: Higher ventilatory efficiency, a continuous non-invasive measure of dead space that does not rely on blood gas measurement, is highly correlated with VD/VT and is independently associated with increased mortality in children with acute hypoxemic respiratory failure. Dead space metrics appear more strongly associated with mortality while OI appears more strongly associated with length of ventilation.