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To characterize the clinical indications, procedural safety, and outcome of critically ill children requiring therapeutic plasma exchange.Retrospective observational study based on a prospective registry.Tertiary and quaternary referral 30-bed PICU.Forty-eight critically ill children who received therapeutic plasma exchange during an 8-year period (2007–2014) were included in the study.Therapeutic plasma exchange.A total of 48 patients underwent 244 therapeutic plasma exchange sessions. Of those, therapeutic plasma exchange was performed as sole procedure in 193 (79%), in combination with continuous renal replacement therapy in 40 (16.4%) and additional extracorporeal membrane oxygenation in 11 (4.6%) sessions. The most common admission diagnoses were hematologic disorders (30%), solid organ transplantation (20%), neurologic disorders (20%), and rheumatologic disorders (15%). Complications associated with the procedure occurred in 50 (21.2%) therapeutic plasma exchange sessions. Overall, patient survival from ICU was 82%. Although patients requiring therapeutic plasma exchange alone (n = 31; 64%) had a survival rate of 97%, those with additional continuous renal replacement therapy (n = 13; 27%) and extracorporeal membrane oxygenation (n = 4; 8%) had survival rates of 69% and 50%, respectively. Factors associated with increased mortality were lower Pediatric Index of Mortality 2 score, need for mechanical ventilation, higher number of failed organs, and longer ICU stay.Our results indicate that, in specialized centers, therapeutic plasma exchange can be performed relatively safely in critically ill children, alone or in combination with continuous renal replacement therapy and extracorporeal membrane oxygenation. Outcome in children requiring therapeutic plasma exchange alone is excellent. However, survival decreases with the number of failed organs and the need for continuous renal replacement therapy and extracorporeal membrane oxygenation.