The inhibition of the cyclooxygenase and/or the lipoxygenase pathways by indomethacin or nordihydroguaiaretic acid during Phase I of estrogen action interfered with estriol-induced initiation of implantation, but not uterine macromolecular uptake and water imbibition. This inhibition of implantation was completely reversed by supplementation with prostaglandin E2 or leukotriene C4. These results suggest that estrogen-induced initiation of implantation in a progesterone-primed uterus is mediated via prostaglandins and leukotrienes as components of Phase I of estrogen action.