OBJECTIVE: To test the hypothesis that RBC transfusion in critically ill children is independently associated with increased mortality and morbidity. DESIGN: Retrospective, descriptive epidemiologic cohort study. SETTING: Single-center experience of a nine-bed pediatric intensive care unit (PICU) facility. PATIENTS: Critically ill children without ongoing active blood loss aged 0[Symbol: see text]months to 18[Symbol: see text]years, excluding prematurely born infants or patients after cardiothoracic surgery, and patients with chronic anemia. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Data of 295 consecutive patients was studied. Of these patients, 13.4% had a Hb concentration less than 9.6 g/dl. Sixty-seven (22.7%) of all patients were transfused, 39 only once. Transfused patients had a higher mortality (16.4 vs. 2.6%, p < 0.001). Mortality seemed related to the number of transfusion (p = 0.002) rather than the pre-transfusion Hb concentration (p = 0.10). Transfused patients required prolonged ventilatory support (11.1 +/- 1.8 vs. +/- 0.3 days, p < 0.001), infusion of vaso-active agents (8.2 +/- 1.8 vs. 2.8 +/- 0.6 days, p < 0.001) and PICU stay (13.0 +/- 1.8 vs. 3.2 +/- 0.2 days, p < 0.001). After multivariate analysis adjusting for age, PIM probability of death, mean TISS-28 score during the first 48 h, post-operative admission, diagnosis of sepsis or trauma or malignancy, pre-transfusion Hb concentration, and RBC transfusion remained independently associated with mortality and morbidity. CONCLUSIONS: RBC transfusion in critically ill children is independently associated with increased mortality and prolonged duration of mechanical ventilation, prolonged infusion of vaso-active agents and prolonged PICU stay.