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The current trend to manage critically ill hematologic patients admitted with acute respiratory failure is to perform noninvasive ventilation to avoid endotracheal intubation. However, failure of noninvasive ventilation may lead to an increased mortality.Retrospective study to determine the frequency of noninvasive ventilation failure and identify its determinants.Medical intensive care unit in a University hospital.All consecutive patients with hematologic malignancies admitted to the intensive care unit over a 10-yr period who received noninvasive ventilation.A total of 99 patients were studied. Simplified Acute Physiology Score II at admission was 49 (median, interquartile range, 39–57). Fifty-three patients (54%) failed noninvasive ventilation and required endotracheal intubation. Their Pao2/Fio2 ratio was significantly lower (175 [101–236] vs. 248 [134–337]) and their respiratory rate under noninvasive ventilation was significantly higher (32 breaths/min [30–36] vs. 28 [27–30]). Forty-seven patients (89%) who failed noninvasive ventilation required vasopressors. Hospital mortality was 79% in those who failed noninvasive ventilation, and 41% in those who succeeded. Patients who failed noninvasive ventilation had a significantly longer intensive care unit stay (13 days [8–23] vs. 5 [2–8]) and a significantly higher rate of intensive care unit-acquired infections (32% compared with 7%). Factors independently associated with noninvasive ventilation failure by multivariate analysis were respiratory rate under noninvasive ventilation, longer delay between admission and noninvasive ventilation first use, need for vasopressors or renal replacement therapy, and acute respiratory distress syndrome.Failure of noninvasive ventilation occurs in half the critically ill hematologic patients and is associated with an increased mortality. Predictors of noninvasive ventilation failure might be used to guide decisions regarding intubation.