The decision whether or not a cell undergoes apoptosis is determined by the opposing forces of pro- and anti-apoptotic effectors. Here we demonstrate genetically that estrogen can tip this balance toward cell survival in uterine epithelial cells by inducing the expression of Birc1s, a family of anti-apoptotic proteins. In neonatal mice, both 17-estradiol and the potent synthetic estrogen diethylstilbestrol (DES), strongly suppress uterine epithelial apoptosis while markedly elevating Birc1 transcript level in an ER--dependent manner. The induction of Birc1s prior to any effect on apoptosis suppression and failure of DES to completely inhibit apoptosis in Birc1a-deficient uterine epithelium, indicate a functional role for Birc1a in estrogen-mediated apoptosis suppression. In ovariectomized adult mice, expression of Birc1s is also induced by ovarian hormones, suggesting a role for these proteins in normal uterine physiology. We propose that by binding to active caspases, Birc1 proteins can eliminate them through proteasome degradation. These results for the first time establish Birc1 proteins as functional targets of estrogen in suppressing apoptosis in the uterus.