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To describe the clinical course, resource use, and mortality of patients with leukemia admitted to the pediatric intensive care unit with sepsis and nonsepsis diagnoses over a 10-yr period.Retrospective analysis.Tertiary medical–surgical pediatric intensive care unit at C.S. Mott Children's Hospital, University of Michigan.All patients with leukemia admitted to the pediatric intensive care unit from January 1, 1998, to December 31, 2008.None; chart review.Clinical course was characterized by demographics, leukemia diagnosis, phase of therapy, leukocyte count on admission, presence of sepsis, steroid administration, intensity of care, and Pediatric Risk of Mortality score on admission to the pediatric intensive care unit. The primary outcome was survival to pediatric intensive care unit discharge. Among 68 single admissions to the pediatric intensive care unit with leukemia during the study period, 33 (48.5%) were admitted with sepsis. Admission to the pediatric intensive care unit for sepsis was associated with greater compromise of hemodynamic and renal function and use of stress dose steroids (p = .016), inotropic and/or vasopressor drugs (p = .01), and renal replacement therapy (p = .028) than nonsepsis admission. There was higher mortality among children with sepsis than other diagnoses (52% vs. 17%, p = .004). Also, mortality among children with sepsis was higher among those with acute lymphoblastic leukemia (60% vs. 44%) compared with acute myelogenous leukemia. Administration of stress dose steroids was associated with higher mortality (50% vs. 17%, p = .005) and neutropenia. Patients with acute lymphoblastic leukemia and sepsis showed the greatest mortality and resource use.Patients with acute leukemia and sepsis had a much higher mortality rate compared with previously described sepsis mortality rates for the general pediatric intensive care unit patient populations. Patients who received steroids had an increased mortality rate, but given the retrospective nature of this study, we maintain a position of equipoise with regard to this association. Variation in mortality and resource use by leukemia type suggests further research is needed to develop targeted intervention strategies to enhance patient outcomes.