Abstract Recent studies of cellular function have demonstrated significant alterations of cell homeostasis during hemorrhagic shock. The progressive depolarization of cell membranes demonstrated in several organs has been attributed to failure of energy-dependent active ion transport. Similar changes in intracellular electrolyte composition have been observed in the red blood cells of some patients in late hemorrhagic shock and in other severely ill patients. The ready availability of isolated cells that do not require extracellular fluid space assessment makes the red blood cell an attractive model for investigating the factors controlling ion movements across the cell wall. It has been suggested that the red blood cell ion abnormalities may represent a generalized cellular response to severe illness. Red blood cell sodium concentration was measured in 145 patients during severe hemorrhagic shock. The direction and magnitude of changes in red blood sodium concentration was correlated with the time course of the shock state. The initial decrease in sodium content was a function of the diminished red blood cell membrane permeability due to a decrease in plasma bicarbonate levels. The subsequent red blood cell sodium uptake above the normal range, not associated with an increase in sodium influx, indicated an impairment of energy-dependent active transport. The observed high sodium concentrations associated with a potassium decrease in the red blood cell appeared to be only one manifestation of a generalized defect in cellular function and composition during severe hemorrhagic shock.