BACKGROUND AND AIMS: Ovarian hormones oppose colorectal cancer, although mechanisms remain undefined. Similarly, the most commonly lost gene products in intestinal neoplasia include guanylin and uroguanylin, paracrine hormones for guanylyl cyclase C (GCC), which recently emerged as a tumor suppressor. However, the molecular intersection between intestinal paracrine and systemic sex hormones opposing intestinal neoplasia has not been explored. METHODS: Intestinal tumorigenesis was quantified in wild type (Gcc(+/+)) and GCC-deficient (Gcc(-/-)) mice carrying mutations in adenomatous polyposis coli (Apc) (Apc(Min/+)) or exposed to the carcinogen azoxymethane (AOM). Proliferation of epithelial cells was examined employing cell cycle markers. RESULTS: Deletion of Gcc increased tumor multiplicity and growth in colons and small intestines, respectively, of Apc(Min) (/+) mice. While changes in multiplicity and growth increased tumor burden, females exhibited approximately 60% (p= 0.040) of the burden in males. Similarly, female Gcc(-/-) mice treated with AOM exhibited approximately 40% (p= 0.048) of the burden in males. Moreover, Gcc deletion promoted epithelial cell proliferation, quantified by increases in beta-catenin, cMyc, cyclin D1, and phosphorylated retinoblastoma protein (pRb), in males but not females. CONCLUSION: There is a previously unappreciated interaction between sex and GCC signaling restricting crypt cell proliferation. Thus, the invariable loss of guanylin and uroguanylin resulting in tumorigenesis is mitigated in females by hormonal components of the ovarian axis. In the context of the universal overexpression of GCC by tumors, these observations highlight the combination of GCC paracrine and ovarian hormones for targeted prevention and therapy of colorectal cancer.