© Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved. Background The effectiveness of humidified high flow nasal cannula (HFNC) in lung transplant (LTx) recipients readmitted to intensive care unit (ICU) because of acute respiratory failure (ARF) has not been determined to date. Methods Retrospective analysis of a prospectively assessed cohort of LTx patients who were readmitted to ICU because of ARF over a 5-year period. Patients received conventional oxygen therapy (COT) or HFNC (Optiflow, Fisher & Paykel, New Zealand) supportive therapy according to the attending physician's criteria. Treatment failure was defined as the need for subsequent mechanical ventilation (MV). Results Thirty-seven LTx recipients required ICU readmission, with a total of 40 episodes (18 COT vs. 22 HFNC). At ICU admission, no differences in comorbidities, pulmonary function, or median sequential organ failure assessment (COT, 4 [interquartile range, 4-6] vs. HFNC, 4 [interquartile range, 4-7]; P = 0.51) were observed. Relative risk of MV in patients with COT was 1.50 (95% confidence interval [95% CI], 1.02-2.21). The absolute risk reduction for MV with HFNC was 29.8%, and the number of patients needed to treat to prevent one intubation with HFNC was 3. Multivariate analysis showed that HFNC therapy was the only variable at ICU admission associated with a decreased risk of MV (odds ratio, 0.11 [95% CI, 0.02-0.69]; P = 0.02). Moreover, nonventilated patients had an increased survival rate (20.7% vs. 100%; relative rate 4.83 [95% CI, 2.37-9.86]; P < 0.001). No adverse events were associated with HFNC use. Conclusion HFNC O 2 therapy is feasible and safe and may decrease the need for MV in LTx recipients readmitted to the ICU because of ARF.