Background: Neuromuscular blockade (NMB) has been shown to improve outcome in acute respiratory distress syndrome (ARDS) in adults, challenging maintaining spontaneous breathing when there is severe lung injury. We tested in a prospective physiological study the hypothesis that continuous administration of NMB agents in mechanically ventilated children with severe acute hypoxemic respiratory failure (AHRF) improves the oxygenation index without a redistribution of tidal volume VT toward non-dependent lung zones. Methods: Oxygenation index, PaO2/FiO(2) ratio, lung mechanics (plateau pressure, mean airway pressure, respiratory system compliance and resistance), hemodynamics (heart rate, central venous and arterial blood pressures), oxygenation [ oxygenation index (OI), PaO2/FiO(2) and SpO(2)/FiO(2)], ventilation (physiological dead space-to-VT ratio) and electrical impedance tomography measured changes in end-expiratory lung volume (EELV), and VT distribution was measured before and 15 min after the start of continuous infusion of rocuronium 1 mg/kg. Patients were ventilated in a time-cycled, pressure-limited mode with pre-set VT. All ventilator settings were not changed during the study. Results: Twenty-two patients were studied (N = 18 met the criteria for pediatric ARDS). Median age (25-75 interquartile range) was 15 (7.8-77.5) weeks. Pulmonary pathology was present in 77.3%. The median lung injury score was 9 (8-10). The overall median CoV and regional lung filling characteristics were not affected by NMB, indicating no ventilation shift toward the non-dependent lung zones. Regional analysis showed a homogeneous time course of lung inflation during inspiration, indicating no tendency to atelectasis after the introduction of NMB. NMB decreased the mean airway pressure (p = 0.039) and OI (p = 0.039) in all patients. There were no significant changes in lung mechanics, hemodynamics and EELV. Subgroup analysis showed that OI decreased (p = 0.01) and PaO2/FiO(2) increased (p = 0.02) in patients with moderate or severe PARDS. Conclusions: NMB resulted in an improved oxygenation index in pediatric patients with AHRF. Distribution of VT and regional lung filling characteristics were not affected.