Because adrenal participation in the defense mechanisms against endotoxic shock is essential for survival, adrenal gland function during reversible endotoxicosis was studied. The injection of E. coli LPS into rats produces an increase in plasma corticosteroids (maximum at 2-4 hr post-endotoxin injection) and ACTH levels (maximum at 2 hr post-endotoxin injection), which return to control values at the recovery phase. Nevertheless, ACTH-induced steroidogenesis in cells isolated from adrenal glands of endotoxemic rats is clearly impaired, even at 2 hr post-endotoxin injection when corticosteroid levels are maximal. During reversible endotoxic shock there is also a depletion of adrenal ascorbic acid (maximum at 2-4 hr post-endotoxin injection) and a decrease in adrenal cytochrome P-450 levels. These data suggest that impairment of the adrenal gland function could involve mechanisms at the receptor level (desensitization by the high plasma ACTH levels or a direct effect of LPS) and/or at post-receptor steps (decrease in adrenal cytochrome P-450 levels related to the diminution in adrenal ascorbic acid content).