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Redox homeostasis is critical for cellular physiological steady state; emerging evidence reveals that excessive lipid peroxides derail redox homeostasis, causing various diseases. However, the role of redox homeostasis in early pregnancy remains largely unknown. It is found that uterine deletion of Glutathione peroxidase 4 (GPX4), a key factor in repairing oxidative damage to lipids, confers defective implantation, leading to infertility. To further pinpoint <jats:italic>Gpx4<\/jats:italic>\u2019s role in different cell types, uterine epithelial\u2010specific <jats:italic>Gpx4<\/jats:italic> is deleted by a lactotransferrin <jats:italic>(Ltf)<\/jats:italic>\u2010<jats:italic>Cre<\/jats:italic> driver; the resultant females are infertile, suggesting increased lipid peroxidation levels in uterine epithelium compromises receptivity and implantation. Lipid peroxidation inhibitor administration failed to rescue implantation due to carbonylation of major receptive\u2010related proteins underlying high lipid reactive oxygen species. Intriguingly, superimposition of Acyl\u2010CoA synthetase long\u2010chain family member 4 (ACSL4), an enzyme that promotes biosynthesis of phospholipid hydroperoxides, along with uterine epithelial GPX4 deletion, preserves reproductive capacity. 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