The effect of dexamethasone administered intraperitoneally on hepatic glucocorticoid receptor binding capacity was measured in adrenalectomized male Swiss Webster mice. The liver content of dexamethasone was also measured. Within 30 min of a 5 micrograms injection, the hepatic content of dexamethasone reached a maximum and fell quickly thereafter. By 6 h the hepatic content of dexamethasone had decreased to 25% of maximum and by 24 h the liver did not contain detectable dexamethasone. At this 24 h point, the glucocorticoid binding capacity was reduced to 50% of control. This decrease reflected down-regulation. Other studies revealed that only glucocorticoids caused this effect and doses of dexamethasone as low as 0.5-5 ng caused a clear down-regulation in binding capacity. Doses that cause receptor down-regulation are also effective at inducing tyrosine aminotransferase, suggesting that dexamethasone down-regulates its own receptors over a physiologically meaningful dosage range. It is concluded that dexamethasone causes a dose-dependent down-regulation of the glucocorticoid receptor in mouse liver.