The steroid hormone progesterone (P) is a critical regulator of uterine receptivity during blastocyst implantation. The hormone acts through nuclear P receptors (PRs) to modulate the expression of specific gene networks in various uterine cell types. To identify the P-regulated pathways underlying uterine receptivity, we previously used oligonucleotide microarrays to analyze uterine mRNA profiles at the time of implantation in response to RU486, a PR antagonist. We reported that the mRNA corresponding to the immune-responsive gene 1 (Irg1), a previously described lipopolysaccharide-inducible gene, is one of the several mRNAs that are markedly down-regulated by RU486 in the preimplantation uterus. In the present study, we performed in situ hybridization to show that P stimulates Irg1 mRNA synthesis in the luminal epithelial cells of uteri of ovariectomized wild-type but not PR knockout mice. We also report that Irg1 mRNA was induced in the luminal epithelium of pregnant uterus between d 3 and 5, overlapping the window of implantation. To investigate the function of Irg1 during implantation, we administered sense or antisense oligodeoxynucleotides into preimplantation mouse uteri. Treatment with antisense oligodeoxynucleotides led to suppression in Irg1 mRNA expression without affecting unrelated mRNAs in the pregnant uterus. This intervention was also accompanied by impairment in embryo implantation, indicating that the phenotype is linked to the suppression of Irg1 mRNA. Collectively, our studies identified Irg1 as a novel target of PR in the pregnant uterus and also revealed that it is a critical regulator of the early events leading to implantation.