Mice deficient in 2 intracellular selenium (Se)-dependent glutathione peroxidases (Gpx1 and Gpx2), by genetically disrupting both alleles of the Gpx1 and Gpx2 genes (Gpx1(-/-)Gpx2(-/-)), develop ileocolitis around weaning. However, decreased Gpx activity in Se-depleted wild-type animals does not produce pathology in the gastrointestinal tract. Because a small percentage of Se-sufficient Gpx1(+/-)Gpx2(-/-) mice have mild ileocolitis, we hypothesized that Se-deficient Gpx1(+/-)Gpx2(-/-) mice will develop severe ileocolitis similarly to the Gpx1(-/-)Gpx2(-/-) mice, and even a trace amount of Gpx2 can protect intestinal mucosa against inflammation. To test our hypothesis, we fed mice at various stages of development with either Gpx1(+/)(-)Gpx2(-/-) or Gpx1(-/-)Gpx2(+/)(-) genotypes an Se-deficient diet for 4-5 wk and assessed the symptoms and pathology. Gpx1(+/)(-)Gpx2(-/-) mice that were deprived of Se in utero or at weaning (18-22 d of age), but not as young adults (31-51 d of age), manifested significantly worse pathology than their Se-sufficient counterparts. Both Gpx1 and Gpx2 activities and mRNA levels were significantly depressed in the ileum of Se-deprived mice. In mice deprived in utero, the pathology included acute inflammation with neutrophil and monocyte infiltration particularly in the colon and was externally manifested by perianal alopecia and ulceration. On the other hand, Gpx1(-/-)Gpx2(+/)(-) mice were unaffected by Se deprivation, regardless of the age of onset. The results show that a trace amount of Gpx2 is protective against ileocolitis, and Se-deficient young Gpx1(+/-)Gpx2(-/-) mice will develop pathology and symptoms similar to Se-adequate Gpx1(-/-)Gpx2(-/-) mice.