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Microvascular alterations may play a role in the development of multiple organ failure in severe sepsis. The effects of red blood cell transfusions on microvascular perfusion are not well defined. We investigated the effects of red blood cell transfusion on sublingual microvascular perfusion in patients with sepsis.Prospective, observational study.A 31-bed, medical-surgical intensive care unit of a university hospital.Thirty-five patients with severe sepsis requiring red blood cell transfusions.Transfusion of one to two units of leukocyte-reduced red blood cells.The sublingual microcirculation was assessed with an Orthogonal Polarization Spectral device before and 1 hr after red blood cell transfusion. Red blood cell transfusions increased hemoglobin concentration from 7.1 (25th–75th percentile, 6.7–7.6) to 8.1 (7.5–8.6) g/dL (p < .01), mean arterial pressure from 75 (69–89) to 82 (75–90) mm Hg (p < .01), and oxygen delivery from 349 (278–392) to 391 (273–473) mL/min·M2 (p < .001). Microvascular perfusion was not significantly altered by transfusion, but there was considerable interindividual variation. The change in capillary perfusion after transfusion correlated with baseline capillary perfusion (Spearman-rho = −.49; p = .003). Capillary perfusion was significantly lower at baseline in patients who increased their capillary perfusion by >8% compared with those who did not (57 [52–64] vs. 75 [70–79]; p < .01), while hemodynamic and global oxygen transport variables were similar in the two groups. Red blood cell storage time had no influence on the microvascular response to red blood cell transfusion.The sublingual microcirculation is globally unaltered by red blood cell transfusion in septic patients; however, it can improve in patients with altered capillary perfusion at baseline.