Progesterone (P ) is required for the preparation of the endometrium for a successful pregnancy. P resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P -progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1 ;Pgr-Cre (Cfp1 ) mice showed impaired P responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1 ectopic lesions showed P resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P -epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.