The survival rate of immunocompromised patients has improved over the past decades in light of remarkable progress in diagnostic and therapeutic options. Simultaneously, there has been an increase in the number of immunocompromised patients with life threatening complications requiring intensive care unit (ICU) treatment. ICU admission is necessary in up to 15% of patients with acute leukemia and 20% of bone marrow transplantation recipients, and the main reason for ICU referral in this patient population is acute hypoxemic respiratory failure, which is associated with a high mortality rate, particularly in patients requiring endotracheal intubation. The application of non-invasive ventilation (NIV), and thus the avoidance of endotracheal intubation and invasive mechanical ventilation with its side effects, appears therefore of great importance in this patient population. Early trials supported the benefits of NIV in these settings, and the 2011 Canadian guidelines for the use of NIV in critical care settings suggest the use of NIV in immune-compromised patients with a grade 2B recommendation. However, the very encouraging results from initial seminal trials were not confirmed in subsequent observational and randomized clinical studies, questioning the beneficial effect of NIV in immune-compromised patients. Based on these observations, a French group led by Azoulay decided to assess whether early intermittent respiratory support with NIV had a role in reducing the mortality rate of immune-compromised patients with non-hypercapnic hypoxemic respiratory failure developed in less than 72 h, and hence conducted a multicenter randomized controlled trial (RCT) in experienced ICUs in France. This perspective reviews the findings from their RCT in the context of the current critical care landscape, and in light of recent results from other trials focused on the early management of acute hypoxemic respiratory failure.