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Fluid overload is common in the critically ill and is thought to contribute to oxygenation failure and mortality. Since increasing disease severity often requires more fluid for resuscitation, it is unclear whether fluid overload is a causative factor in morbidity or is simply an indicator of disease severity.Investigate the association between fluid overload and oxygenation while controlling for severity of illness by daily Pediatric Logistic Organ Dysfunction scores.Retrospective chart review, tertiary children’s hospital.The oxygenation index, fluid overload percent, and daily Pediatric Logistic Organ Dysfunction scores were obtained in a retrospective chart review of 80 patients (mean age 58.7 ± 73.0 months) with respiratory failure. Univariate and multivariate approaches were used to assess the independent relation between fluid overload percent and duration of stay and ventilation.None.Higher peak fluid overload percent predicted higher peak oxygenation index, independent of age, gender, and Pediatric Logistic Organ Dysfunction (p = .009). Fluid overload percent ≥15% on any given day was also independently associated with that day’s oxygenation index, controlled for age, gender, and Pediatric Logistic Organ Dysfunction (p < .05). Peak fluid overload percent and severe fluid overload percent (≥15%) were both independently associated with longer duration of ventilation (p = .004, p = .01), and pediatric intensive care unit (p = .008, p = .01) and hospital length of stay (p = .02, p = .04), controlled for age, gender, Pediatric Logistic Organ Dysfunction, and in the case of ventilation, respiratory admission.This is the first study to report that positive fluid balance adversely affected the pediatric intensive care unit course in children who did not receive renal replacement therapy. While timely administration of fluids is lifesaving, positive fluid balance after hemodynamic stabilization may impact organ function and negatively influence important outcomes in critically ill patients.