Background/Purpose: Inhalation injury, flame burn exceeding 30%, and age under 48 months all have been cited as independent risk factors for mortality; the combination of all 3 risk factors is unusual. The authors have experienced an overall reduction in mortality rate and chose to examine this high-risk group to define techniques useful in improving outcome in pediatric burns. Methods: A review was done of children with all 3 risk factors over a recent 9-year interval. All were treated with a system of care emphasizing precise fluid repletion, early wound excision and closure, and avoidance of injurious pulmonary inflating pressures and concentrations of oxygen. Data are expressed as mean +/- SD. Results: There were 26 children admitted with all 3 risk factors. Their average age was 2.1 +/- 1.1 years (range, 5 weeks to 3.7 years), and burn size was 61% +/- 21% (range, 30% to 98%) of the body surface. All required mechanical ventilation for an average of 28 +/- 4.5 days (range, 7 to 74 days). Two children underwent tracheostomy; all others were treated with protracted oral intubation. Inhaled nitric oxide (NO) was used in 3 children, all of whom were considered for extracorporeal membrane oxygenator (ECMO) support, although none went on to ECMO. Only 7 children (27%) never had any bacteremia. Ventilator-related pneumonia occurred in 8 children (31%). Total lengths of stay, including acute and rehabilitation hospitalizations, averaged 105 +/- 10 days (1.87 +/- 0.2; range, 0.66 to 4.8 days per percent burn). After exclusion of 1 child with a 98% third-and fourth-degree burn, pre-hospital cardiac arrest, and anoxic brain injury who had support withdrawn at 6 hours, all children survived to discharge; 23 followed up in our clinic currently are alive and well with no overt residual respiratory insufficiency. Conclusion: A high rate of survival can be expected in young children with large burns and inhalation injury. J Pediatr Surg 36:1308-1312.