Sepsis is known to alter red blood cell (RBC) deformability, and this change in flexibility may play a role in the pathophysiology of the hemodynamic alterations characteristic of the septic syndrome. The etiology of this red cell change is unclear. This study evaluates erythrocyte size and cell membrane fluidity during clinical (septic surgical patients) and experimental (endotoxin incubation) sepsis. Membrane lipid viscosity was assessed by fluorescent spectroscopy. Mean corpuscular volume and hemoglobin concentration was determined by automated counter. There was a significant increase in erythrocyte membrane lipid viscosity (P < 0.001) in both the clinical and experimental septic models. No difference was detected, however, in RBC mean corpuscular volume or hemoglobin concentration. These findings suggest that sepsis-induced alterations in erythrocyte deformability are due primarily to an increase in the membrane lipid viscosity and are unrelated to alterations in the cell surface area to volume ratio.