Glutathione (GSH) is the most important cytosolic antioxidant. Since GSH levels are decreased with age, we hypothesized that T-lymphocytes from old mice would be more sensitive to oxidative stress. T-lymphocytes from young and old mice were exposed to hypoxanthine/xanthine oxidase, and lymphocyte viability, proliferation, GSH content, and calcium signaling were measured. Before exposure, proliferation of T-lymphocytes from young mice was greater than that of old; following exposure, the converse was true. This was in spite of the fact that old mice had lower total GSH levels and greater levels of glutathione disulfide. After oxidative challenge, intracellular calcium responses to anti-CD3 were decreased in naive T-lymphocytes from all mice, while memory lymphocytes were less affected. Higher proportions of memory lymphocytes in old mice resulted in their greater overall preservation of lymphocyte function following oxidative injury, contrary to expectations that lower lymphocyte GSH content with age would increase susceptibility to oxidative stress.