Splenectomized and adrenalectomized-splenectomized dogs, anesthetized with pentobarbital, were bled so that the role of cortisol in restitution of blood volume could be examined. Intact dogs and adrenalectomized dogs infused with cortisol at a high rate (17 mug/min) showed restoration of blood volume and plasma protein at 24 h, preceded by an early increase in plasma osmolality. Adrenalectomized dogs infused with cortisol at basal rates (2 mug/min) showed no increase in plasma osmolality and no restoration of blood volume or plasma protein at 24 h unless extracellular fluid volume was expanded by exogenous fluid. It is concluded that hemorrhage leads to an increase in extracellular osmolality mediated in part by increased cortisol concentrations. As a consequence, there is a shift of intracellular fluid to the interstitium. The resulting increase in interstitial pressure accelerates lymphatic movement of interstitial protein to the vascular system. This results in a reequilibration of extracellular fluid toward the plasma, thus completing the restitution of blood volume. The osmotically active agents mobilized by cortisol do not appear to be glucose, sodium, or potassium.