Extracellular glutathione peroxidase (EGPx) is a unique seleno-enzyme found in plasma and other extracellular fluids. Based on the disappearance of plasma EGPx activity in nephrectomized animals and the high level of EGPx mRNA in renal tissue, it was previously concluded that the kidney was the major source of plasma EGPx activity. We have previously shown that humans with renal failure receiving chronic dialysis treatment possess 42% plasma GPx activity. We examined the effect of nephrectomy and renal transplantation on plasma GPx activity. Nephrectomized patients have 22% plasma GPx activity, which increases to ≥ 100% of normal within 2 weeks following transplantation.In situ hybridization studies have shown that EGPx message is predominantly localized to the proximal convoluted tubules. We have determined that the EGPx mRNA is localized specifically to the S1 and S2 segments of the proximal tubules. We therefore examined the effect of nephrotoxic agents known to affect proximal tubule function. In rabbits, a nephrotoxic dose of cephaloglycin (300 mg/kg) caused a 52% decrease in plasma GPx activity within 24 hours. This effect was prevented by concomitant treatment with probenecid. Patients receiving ifosfamide chemotherapy were found to have lower levels of plasma GPx activity. Three patients with Fanconi syndrome associated with ifosfamide therapy had 50, 56, and 23% of control plasma GPx activity. After resolution of the Fanconi syndrome in one patient, plasma GPx activity returned to normal within one month. We speculate that plasma GPx activity may be a sensitive and early indicator of damage to renal proximal tubules.