One of the major hallmarks of uterine diseases is disruption of ovarian steroid hormone control of uterine cell proliferation and differentiation. Estrogen (E2) stimulates proliferation of uterine epithelial cells while progesterone (P4) is inhibitory to E2-mediated proliferation of the epithelium. Mitogen inducible gene 6 (Mig-6) is an important mediator of P4 signaling to inhibit E2 signaling in the uterus. Uterine-specific knockout of Mig-6 caused endometrial P4 resistance and infertility. Levels of ErbB2 (also known as HER2) and phospho-ERK1/2 are significantly higher in Mig-6 knockout mice as well as infertile women with endometriosis. To determine the interplay between Mig-6 and the Erbb2 signaling pathway in the uterus, we generated mice with Mig-6 and Erbb2 conditionally ablated in progesterone receptor-positive cells (Pgrcre/+ Mig-6f/f Erbb2f/f; Mig-6d/d Erbb2d/d). Mig-6d/d mice were infertile whereas control and Mig-6d/d Erbb2d/d mice exhibited normal fecundity. The uterine horns of Mig-6d/d mice had no implantation sites, whereas control and Mig-6d/d Erbb2d/d mice had averaged implantation sites. Additionally, aberrant increment of epithelial proliferation in uterus of Mig-6d/d mice did not show in Mig-6d/d Erbb2d/d mice uterus at pre-implantation stage. Microarray analysis revealed that almost altered genes in Mig-6d/d mice were recovered their expression levels in Mig-6d/d Erbb2d/d mice. The altered pathways such as cell-cycle control, DNA replication, and modification processes by Mig-6 ablation were rescued in Mig-6d/d Erbb2d/d mice. The infertility seen in Mig-6d/d mice is recovered in Mig-6d/d Erbb2d/d mice. These results suggest that Mig-6 mediates a critical P4 function to inhibit E2 signaling by inhibiting ErbB2 signaling. As MIG-6 is a mediator of P4 signaling, the activity of which can suppress unopposed-E2 signaling, our studies provide a potential new drug target for the intervention of female infertility.