Previous studies have suggested that increases in extracellular osmolality mediate a shift of intracellular fluid into the interstitium following 10% hemorrhage. This unidirectional fluid movement is required for full restitution of blood volume (BV) and for cardiovascular stabilization. The extent to which this mechanism acts in larger hemorrhages was examined in these studies. Forty-two dogs were studied 3 weeks after splenectomy. Twenty were anesthetized with pentobarbital, the others were studied awake. Hemorrhages of 10% (7.5 ml/kg, 15 dogs), 20% (15 ml/kg, 13 dogs), and 30% (22.5 ml/kg, 15 dogs) were carried out over 3 minutes.Patterns of changes in osmolality, total plasma protein content, and blood volume were identical in the two groups, although osmolality was significantly greater during the first 2 hours in anesthetized dogs. Osmolality increased with increasing degrees of hemorrhage, providing an increasing driving force for fluid shifts. Restitution of BV was significantly greater after 20% hemorrhage than after 10% hemorrhage. However, restitution of BV after 30% hemorrhage was no greater than after 10% hemorrhage. Patterns of protein restitution paralleled changes in BV. Cunningham, Shires, and Wagner (7) reported fluid shifts into cells after a 30% hemorrhage associated with a fall in membrane potential. It thus appears likely that a fluid shift out of cells in response to increased osmolality is offset by shifts into cells as the magnitude of hemorrhage becomes large. This failure of homeostatic restoration of BV with consequent failure of cardiovascular stabilization may represent an early event in the development of hemorrhagic shock.