Background: Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for life-threatening respiratory or circulatory failure. Although outcomes are favorable with short-term ECMO therapy, data on the outcomes of prolonged ECMO therapy in children are very limited. This study aimed to study morbidity and mortality associated with prolonged ECMO therapy (<28 days) in children with refractory cardiac or pulmonary failure. Methods: We conducted a retrospective review of all children ≤18 years supported with ECMO for <28 days between January 1991 and September 2011 at the Arkansas Children's Hospital. The data collected in our study included patient demographic information; diagnosis; indication for ECMO; ECMO support details; medical and surgical history; laboratory, microbiologic, and radiographic data; information on organ dysfunction; complications; and patient outcomes. The outcome variables evaluated in this report included survival to ECMO decannulation, survival to hospital discharge, and current survival with emphasis on neurologic, renal, pulmonary, and other end organ function. Results: During the study period, 984 events in 951 patients were supported with ECMO with a 30-day survival of 666 events (68%). Only 22 ECMO runs were <28 days and were eligible for inclusion in this report. The longest ECMO run in our series was 1,206 hours (50 days). The average length of ECMO run in this cohort was 855 ± 133 hours, with a mean intensive care unit length of stay of 56 ± 27 days. Ten patients (45%) were successfully decannulated from ECMO. Six patients (27%) were alive 30 days after decannulation, and only 4 patients (19%) survived to hospital discharge. Of the 4 survivors, only 3 patients (14%) are living to date. Of the 3 living children, 2 have significant neurologic issues with brain atrophy and developmental delay, and 1 is awaiting renal transplant; all 3 survivors have chronic lung disease. Conclusions: This case series highlights that the prolonged use of ECMO in children with refractory cardiac failure, respiratory failure, or both is associated with low survival. Furthermore, it suggests that the survivors of prolonged ECMO runs have significant long-term sequelae.