Objectives: Small studies of extracorporeal membrane oxygenation (ECMO) support for children with refractory septic shock (RSS) suggest that high-flow (≥ 150 mL/kg/min) venoarterial ECMO and a central cannulation strategy may be associated with lower odds of mortality. We therefore aimed to examine a large, international dataset of venoarterial ECMO patients for pediatric sepsis to identify outcomes associated with flow and cannulation site., Design: Retrospective analysis of the Extracorporeal Life Support Organization (ELSO) database from January 1, 2000, to December 31, 2021., Setting: International pediatric ECMO centers., Patients: Patients 18 years old young or younger without congenital heart disease (CHD) cannulated to venoarterial ECMO primarily for a diagnosis of sepsis, septicemia, or septic shock., Interventions: None., Measurements and Main Results: Of 1242 pediatric patients undergoing venoarterial ECMO runs in the ELSO dataset, overall mortality was 55.6%. We used multivariable logistic regression analyses to evaluate explanatory factors associated with adjusted odds ratios (aORs) and 95% CI of mortality. In the regression analysis of data 4 hours after ECMO initiation, logarithm of the aOR, plotted against ECMO flow as a continuous variable, showed that higher flow was associated with lower aOR of mortality (p = 0.03). However, at 24 hours, we failed to find such a relationship. Finally, peripheral cannulation, as opposed to central cannulation, was independently associated with greater odds of mortality (odds ratio, 1.7 [95% CI, 1.1-2.6])., Conclusions: In this 2000-2021 international cohort of venoarterial ECMO for non-CHD children with sepsis, we have found that higher ECMO flow at 4 hours after support initiation, and central- rather than peripheral-cannulation, were both independently associated with lower odds of mortality. Therefore, flow early in the ECMO run and cannula location are two important factors to consider in future research in pediatric patients requiring cannulation to venoarterial ECMO for RSS., Competing Interests: Dr. Stark’s institution received funding from the National Institutes of Health/National Institute of General Medical Sciences (R35 GM138191). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2025 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)