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However, developing genetically modified mouse models to analyze various combinations of mutations is extremely labor\u2010intensive and time\u2010consuming. To address these problems, we developed a novel method for in vivo multiplexed genome editing of the murine uterus to model human endometrial carcinoma (EMC). To do this, we injected a CRISPR\u2010Cas9 ribonucleoprotein complex into the uterine cavity of adult female mice, followed by electroporation. Evaluation of reporter mice demonstrated that genome editing occurred specifically in uterine epithelial cells, which are the origin of EMCs. Simultaneous targeting of <jats:italic>Pten<\/jats:italic>\/<jats:italic>Trp53<\/jats:italic>\/<jats:italic>Lkb1<\/jats:italic>, or targeting of <jats:italic>Pten<\/jats:italic>\/<jats:italic>Lkb1<\/jats:italic> along with the <jats:italic>Ctnnb1<\/jats:italic>\u0394Ex3 mutation, resulted in efficient generation of invasive tumors in wild\u2010type females within 3\u00a0months. 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