This study examined the effects of dexamethasone on the glucose, lactate, and insulin dyshomeostasis of endotoxicosis in the rat. To assess the effects of dexamethasone on carbohydrate dyshomeostasis, sequential measurements of plasma glucose and lactate were made in vivo. The effects of dexamethasone on endotoxin-induced portal and systemic hyperinsulinemia also were evaluated in vivo. The ability of dexamethasone to alter the insulin hypersecretory state of the endotoxic pancreas was evaluated by using the in vitro perfused rat pancreas. Endotoxicosis caused severe hypoglycemia and hyperlactacidemia in the pentobarbital-anesthetized rat. Dexamethasone prevented the hypoglycemia, significantly reduced the hyperlactacidemia, and prevented endotoxin-induced hyperinsulinemia in vivo. Dexamethasone reduced endotoxin-induced pancreatic hypersecretion of insulin when administered as a pretreatment 1 h prior to endotoxin treatment; however, when administered as a cotreatment with endotoxin, no significant reduction of insulin hypersecretion occurred. The results of this study suggest that the ameliorating effects of dexamethasone on glucose and lactate dyshomeostasis occur not only at the peripheral tissue level, but also through effects on insulin secretion.