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Background: Red blood cell (RBC) transfusions are associated with risks including immunological reactions and volume overload. Current guidelines suggest a restrictive transfusion strategy in most patients with sepsis but based on previous randomized controlled trials and observational studies, there are still uncertainties about the safety in giving low-grade RBC transfusions to patients with sepsis. Methods: Critically ill patients with severe sepsis or septic shock admitted to a university hospital intensive care unit between 2007 and 2018 that received less or equal to 2 units of RBCs during the first 5 days of admission were propensity score matched to controls. Outcomes were 90- and 180-day mortality, highest acute kidney injury network (AKIN) score the first 10 days, days alive and free of organ support the first 28 days after admission to the intensive care unit and highest sequential organ failure assessment score (SOFA-max). Results: Of 9490 admissions, 1347 were diagnosed with severe sepsis or septic shock. Propensity-score matching resulted in two well-matched groups with 237 patients in each. The annual inclusion rate in both groups was similar. The median hemoglobin level before RBC transfusion was 95 g/L (interquartile range 88–104) and the majority of the patients were transfused in first 2 days of admission. Low-grade RBC transfusion was associated with increased 90- and 180-day mortality with an absolute risk increase for death 9.3% (95% confidence interval: 0.6–18%, P = 0.032) and 11% (95% confidence interval: 1.7–19%, P = 0.018), respectively. Low-grade RBC transfusion also correlated with increased kidney, circulatory and respiratory failure and higher SOFA-max score. Conclusions: Low-grade RBC transfusion during the first 5 days of admission was associated with increased mortality and morbidity in a liberal transfusion setting. The results support the current practice of a restrictive transfusion strategy in septic critically ill patients. [ABSTRACT FROM AUTHOR]