Purpose: Transfusing red blood cells (RBCs) in non-bleeding critically ill patients once the haemoglobin meets a certain threshold is the standard of care, despite the lack of robust data suggesting improved outcomes with this practice. Our aim was to critically examine if there are discernible physiological benefits to RBC transfusion in patients with respiratory failure, individuals who are susceptible to transfusion-related adverse events. Materials and methods: This is a single-centre, cross-sectional study including mechanically ventilated adults who were not bleeding and underwent an isolated RBC transfusion for a haemoglobin level of <7 g/dl identified on a routine blood draw. We recorded vital signs and variables related to organ function (gas exchange, laboratory data and severity of illness) in the six hours pre-and post-transfusion that might plausibly benefit from the transfusion. Results: Seventy-four patients met the inclusion criteria. There were no improvements in vital signs, laboratory data, vasopressor requirements and overall illness severity after RBC transfusion. Gas exchange as measured by the PaO2/FiO2 ratio, however, worsened (pre-transfusion 233±106, post-transfusion 199±92; p=0.01), an association which held after multivariate adjustment in the two time periods. Conclusions: We found no change in common physiological parameters after RBC transfusion in patients intubated for hypoxaemic respiratory failure. In fact, the PaO2/FiO2 ratio worsened slightly. This might be related to an adverse effect of the transfusion, perhaps mediated by a volume effect or direct lung injury. These data provide preliminary rationale of the nonutility of RBC transfusion based purely on an arbitrary haemoglobin threshold in this patient population. © 2021, Netherlands Society of Intensive Care. All rights reserved.