Background and aims: Hemophagocytic lymphohistiocytosis (HLH) is an autoimmune phenomenon with impaired cytotoxic T-cell and natural killer cell function, excessive macrophage activity, cytokine release and global inflammation. Frequency is estimated at 1:3000 admissions to tertiary pediatric centers. Aims: Clinical presentation varies, and appropriate diagnosis requires a high degree of clinical suspicion. Methods: Three children (aged 14 mo, 35 mo and 9 yr) were admitted to the PICU between 2007 and 2013 with acute respiratory failure (ARF) of unknown etiology, elevated transaminases and thrombocytopenia. Each failed conventional ventilation, and 2/3 failed high-frequency oscillatory ventilation. The Institutional Review Board waived the need for informed consent. Results: Venovenous extracorporeal life support (ECLS) was initiated in each patient. Two were placed on ECLS on PICU day 3. The third was transitioned on PICU day 10. Oxygenation indices prior to initiation of ECLS ranged from 29 to 106 with mean airway pressures between 22 and 38. One patient required vasoactive support with epinephrine, dopamine and milrinone prior to ECLS, and two required vasoactive support during ECLS. While on ECLS, each child underwent bone marrow biopsy which confirmed hemophagocytosis. All had HLH treatment initiated while on ECLS. Patients were successfully decannulated after 79.5 – 116 hours on ECLS and eventually discharged home in good condition. Conclusions: ECLS is an effective mode of support to allow stabilization in critically ill children with ARF of unclear etiology. Invasive diagnostic procedures such as bone marrow biopsy can be well tolerated during anticoagulation. ECLS was successfully used to allow diagnosis and initiation of treatment in new-onset HLH.