Glutathione (GSH) complexes of mercury (Hg) may play a significant role in the tissue accumulation and excretion of this metal. As a test of this hypothesis, the effect of GSH depletion on Hg deposition in tissues was measured in rats. Tissues were depleted of GSH by ip administration of compounds that form mercapturic acid derivatives. GSH was determined colorimetrically. Hg was administered as [203Hg]methylmercuric chloride, 1.0 mg/kg ip, and total Hg content of tissues measured by gamma scintillation spectrometry. When methylmercury was administered 0.5 hr after diethylmaleate (DEM) or propylene glycol (PG), significantly lower Hg concentrations in kidney and brain of DEM-treated animals were observed at 2.5 hr. While liver, lung, kidney and brain followed a dose-response relationship between DEM administered and GSH depletions, only kidney consistently displayed a corresponding dose-dependent effect of DEM on Hg concentration. Kidneys of rats given 0.31, 0.62, 1.55 and 3.10 mmol/kg of DEM in PG solution had GSH concentrations at 2.5 hr that were 102, 96, 72 and 47% of control values, respectively; and 76, 74, 38 and 28% of the Hg concentrations of kidneys from corresponding methylmercury-treated PG controls. When methylmercury was given at 0.5, 1.0, 2.0, 3.0 and 4.0 hr after 2.48 mmol/kg of DEM, kidney GSH concentrations at 2 hr after Hg administration were 57, 75, 80, 83 and 107%; and Hg concentrations were 20, 44, 53, 73 and 106% of controls for each respective time point. In addition to DEM, sodium maleate, acrylamide and benzyl chloride each lowered renal GSH concentrations and resulted in decreased deposition of Hg in kidney. Oxidation of renal GSH by sodium tetrathionate produced the same effect as the depleting agents on kidney Hg levels. These results suggest that renal GSH is a determinant in the deposition of Hg in kidney. (Supported by Research Grant OH-00315 from NIOSH and Training and Research Grants ES-00084 and ES-00002 from NIEHS, USDHEW.)