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Glutathione (GSH) is a potent endogenous antioxidant that protects major organs from oxidant injury. However, present nutrition regimens may inadequately support tissue stores of this tripeptide during critical illness. To determine whether GSH reserves can be enhanced in vivo with intravenous (IV) supplements, rats underwent central venous catheterization, were given chow and water ad libitum during a 2-day recovery period, and were then randomized to receive one of three treatments as an IV bolus: (1) dextrose, (2) glutathione (GSH), or (3) glutathione monoethyl ester. GSH monoethyl ester is transported into cells more easily than is GSH. Tissue and plasma samples were analyzed for GSH at 2 and 4 hours after drug administration. Liver, renal, and ileal mucosal GSH were significantly increased in the GSH-monoethyl ester rats compared with dextrose-treated animals. In addition, plasma GSH was dramatically increased after monoester injection. In contrast, GSH administration depressed liver GSH stores and did not significantly affect GSH concentration in the other organs analyzed. Plasma GSH concentration was elevated 2 hours after GSH administration. We conclude that: (1) the monoethyl ester of glutathione can be used in vivo to enhance tissue and plasma GSH concentration and (2) IV GSH administration does not significantly increase tissue GSH levels and may paradoxically depress hepatic GSH in normal rats. Because the malnourished and critically ill are likely to have depleted GSH stores, nutrition strategies that include the provision of GSH monoester may lend additional support to those organs that are at risk for injury from oxygen free radicals during catabolic states.