Objective: To describe the effects of prone positioning on airway management, mechanical ventilation, enteral nutrition, pain and sedation management, and staff utilization in infants and children with acute lung injury. Design: Secondary analysis of data collected in a multiple-center, randomized, controlled clinical trial of supine vs. prone positioning. Setting: Seven pediatric intensive care units located in the United States. Patients: One hundred and two pediatric patients (51 prone and 51 supine) with acute lung injury. Interventions: Patients randomized to the supine group remained supine. Patients randomized to the prone group were positioned prone per protocol during the acute phase of their illness for a maximum of 7 days. Both groups were managed using ventilator and sedation protocols and nutrition and skin care guidelines. Measurements and Main Results: Airway management and mechanical ventilatory variables before and after repositioning, enteral nutrition management, pain and sedation management, staff utilization, and adverse event data were collected for up to 28 days after enrollment. There were a total of 202 supine-prone-supine cycles. There were no differences in the incidence of endotracheal tube leak between the two groups (p = .30). Per protocol, 95% of patients remained connected to the ventilator during repositioning. The inadvertent extubation rate was 0.85 for the prone group and 1.03 for the supine group per 100 ventilator days (p = 1.00). There were no significant differences in the initiation of trophic (p = .24), advancing (p = .82), or full enteral feeds (p = .80) between the prone and supine groups; in the average pain (p = .81) and sedation (p = .18) scores during the acute phase; and in the amount of comfort medications received between the two groups (p = .91). There were no critical events during a turn procedure. While prone, two patients experienced an obstructed endotracheal tube. One patient, supported on high-frequency oscillatory ventilation, experienced persistent hypercapnea when prone and was withdrawn from the study. The occurrence of pressure ulcers was similar between the two groups (p = .71). Compared with the supine group, more staff (p ≤ .001) and more time were necessary to reposition patients in the prone group. Conclusions: Our data show that prone positioning can be safely performed in critically ill pediatric patients and that these patients can be safely managed while in the prone position for prolonged periods of time.