We previously revealed that glucocorticoids such as cortisol and cortisone may also regulate sodium and fluid balance in healthy subjects. We also reported that dexamethasone administration to mice initially increased urinary sodium excretion and urine volume and reduced skin sodium and water content in the early phase of administration and that chronic dexamethasone injection only decreased skin sodium and water content. However, it remains to be clarified which organ, kidney or skin, is responsible for the initial sodium and water loss at initial dexamethasone injection. In the present study, we examined the effects of dexamethasone on skin sodium and water content in bilateral nephrectomized mice. In the sham-operated group, dexamethasone (1 mg/kg/day, s.c.) significantly increased urinary sodium excretion and urine volume and decreased skin sodium and water content 24 hours after the injection. Dexamethasone did not affect plasma sodium concentration and osmolarity. In bilateral nephrectomy groups, dexamethasone did not alter skin sodium and water content. These findings suggest that glucocorticoid originally increases urinary sodium excretion and urine volume, which decreases skin sodium and water loss to compensate for renal sodium and water loss. In order to elucidate the mechanisms of sodium and fluid homeostasis, it may be necessary to examine skin and glucocorticoids in addition to the known hormones and kidney systems.