Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have demonstrated that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk, though it is unknown if they are effective in women with Lynch syndrome. In the present study, the short-term effects of progestin-containing OCP or depo-medroxyprogesterone acetate (depoMPA) on the endometrium in women with Lynch syndrome were examined using endometrial proliferation as the primary endpoint. The cover micrograph depicts a focus of complex endometrial hyperplasia in a post-treatment endometrial biopsy of a nonresponder (H&E; 4×). In most of the women, both depoMPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action, demonstrating that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins and suggesting that OCP and depoMPA may be reasonable chemopreventive agents in this high-risk patient population. See the article by Lu et al. (beginning on page 774) for more information.