The role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women's Health Initiative (WHI) study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens (CEE) plus the synthetic progestin medroxyprogesterone acetate (MPA), compared to CEE-only treatment. These findings continue to be discussed and it remains to be clarified whether the results obtained for MPA in the WHI study are directly applicable to other progestins employed in hormone therapy. In this study we compared in a mouse model the effects of the synthetic progestins, MPA and drospirenone, in two major target organs: the uterus and the mammary gland. As quantitative measures of progestin activity, we analyzed maintenance of pregnancy, ductal sidebranching in the mammary gland, proliferation of mammary and uterine epithelial cells, as well as target gene induction in both organs. The outcome of this study is that not all synthetic progestins exhibit the same effects. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, drospirenone behaved similarly to the natural hormone, progesterone, and exhibited uterine activity at doses lower than those leading to considerable proliferative effects in the mammary gland. We hypothesize that the safety of combined hormone therapy in postmenopausal women may be associated with a dissociation between the uterine and mammary gland activities of the progestin component.