Rat renal function was evaluated during acute depletion of glutathione (GSH) produced by different doses of diethyl-maleate (DEM). Significant alterations in renal function were observed when the GSH level diminished. The replenishment of GSH and the restoration of renal function were also investigated at various times after the injection. Similar time courses were observed of both the GSH level and renal functions, but the former was shortest. This suggests that the restoration to normal of GSH renal content was necessary in order to regain appropriate kidney function. Furthermore, the fact that impairment of sodium excretion occurred simultaneously with GSH depletion may be considered as evidence of the first event in GSH protective action. It may be hypothetized that the thick ascending limb is the principal renal target for this deficiency.