BACKGROUND Red blood cell transfusion is commonly used to augment systemic oxygen delivery to supranormal levels in patients with sepsis. However, clinical studies have not consistently demonstrated that this therapeutic maneuver is accompanied by an increase in oxygen utilization at either the whole-body level or within individual organs. OBJECTIVE To determine the effect of red blood cell transfusion on gastrointestinal and whole-body oxygen uptake. METHODS Prospective, controlled, interventional study. METHODS Multidisciplinary intensive care unit of a tertiary care teaching hospital. METHODS Twenty-three critically ill patients with sepsis undergoing mechanical ventilation. RESULTS Systemic oxygen uptake was measured by indirect calorimetry and calculated by the Fick method. Gastric intramucosal pH as measured by tonometry was used to assess changes in splanchnic oxygen availability. Measurements were made prior to transfusion of 3 U of packed red blood cells. These were then repeated immediately following transfusion, as well as 3 and 6 hours later. There was no increase in systemic oxygen uptake measured by indirect calorimetry in any of the patients studied for up to 6 hours posttransfusion (including those patients with an elevated arterial lactate concentration). However, the calculated systemic oxygen uptake increased in parallel with the oxygen delivery in all the patients. More importantly, we found an inverse association between the change in gastric intramucosal pH and the age of the transfused blood (r = -.71; P < .001). In those patients receiving blood that had been stored for more than 15 days, the gastric intramucosal pH consistently decreased following the red blood cell transfusion. CONCLUSIONS We failed to demonstrate a beneficial effect of red blood cell transfusion on measured systemic oxygen uptake in patients with sepsis. Patients receiving old transfused red blood cells developed evidence of splanchnic ischemia. We postulate that the poorly deformable transfused red blood cells cause micro-circulatory occlusion in some organs, which may lead to tissue ischemia in some organs.