Oral iron-supplementation is a general practice to correct iron deficiency anemia. Exposure of iron-deficient intestine to large doses of iron is known to induce oxidative damage, leading to loss of functional integrity, and reduced mucosal cell turnover. Conditioning of intestine with anti-oxidants during iron administration was shown to suppress iron-induced oxidative damage. Zinc is known to protect cells from peroxidative damage by inducing metallothionein and maintaining the sulfhydryl group stability. Nevertheless, co-administration of iron and zinc may antagonize each other with respect to absorption. In the present study, we show that combined supplementation of iron and zinc though marginally inhibits iron uptake significantly attenuates the oxidative stress by induction of metallothionein and elevating the levels of GSH. Further, presence of zinc in situ reduced the iron-induced hydroxyl radical production in the intestinal mucosa, as assessed by EPR spectroscopy. These results strongly suggest a protective role for zinc on iron-induced oxidative stress, which might have implications in anemia control programs. (C) 2004 Elsevier Inc. All rights reserved.