The effect of lowering renal cortical sulfhydryl concentration on development of acute renal failure (ARF) was evaluated in rats receiving HgCl2 (15 mg/kg body weight, im). Within 90 min after HgCL2 injection urine flow rate and fractional excretion of sodium (FENa) were significantly elevated above control levels, and they remained elevated throughout the 3-h experimental period. Urine flow rate and FENa were not significantly elevated above control levels in animals injected with diethyl maleate (3 mmol/kg, ip) 30 min before and 90 min after HgCl2 (DEM/HgCl2). Administration of DEM alone did not alter renal function. Although lower than control levels, concentrations of protein-bound sulfhydryl groups (PBSH) were comparable in HgCl2- and DEM/HgCl2-treated animals. In contrast, concentrations of nonprotein sulfhydryl groups (NPSH) were 62% lower in DEM/HgCl2 animals than in those treated with HgCl2 alone. Similarly, Hg accumulation was 54% lower in DEM/hgCl2-treated animals than in animals treated with HgCl2 alone. These results suggest that NPSH play an important role in Hg uptake and subsequent development of Hg toxicity.