Groups of splenectomized dogs were treated with weekly im doses of a potent glucocorticoid, methylprednisolone acetate (MPA; 2.5 mg/kg) or MPA-vehicle (controls) to determine if glucocorticoid-induced adrenocortical suppression would alter the restitution of blood volume in response to a 7.5 ml/kg hemorrhage. Five of the MPA-treated dogs were infused with cortisol (17 μg/min) for 2 hr beginning with the onset of hemorrhage. Blood volume restitution at 24 hr post-hemorrhage was reduced (P<0.05) in MPA-treated (46.5 ± 4.7%) or MPA-treated- cortisol infused (69.8 ± 9.7%) dogs as compared to controls (114 ± 11.8%). Hemorrhage was associated with a rapid increase in plasma immunoreactive (i) ACTH and cortisol concentrations in controls. In contrast, MPA treatment lowered baseline plasma iACTH and cortisol concentrations and prevented increases in either hormone following hemorrhage. Infusion of cortisol in one group of MPA-treated dogs gradually raised plasma cortisol concentrations but to lower (P<0.05) concentrations than measured in controls. Plasma aldosterone and glucose concentrations were not altered by MPA-treatment. Plasma osmolality increased to a greater (P<0.05) extent after hemorrhage in controls than in either group of MPA-treated dogs. It is concluded that glucocorticoid-induced adrenocortical suppression impairs the normal blood volume restitution process after moderate hemorrhage. The failure of cortisol infusion to fully restore restitution after MPA treatment may indicate that the pattern of the plasma cortisol response to hemorrhage is important in activating the restitution process or that MPA treatment diminishes non-cortisol dependent factors involved in restitution.