Asoprisnil, its active metabolite J912, and J956 are novel SPRMs that exhibit partial (mixed) agonist/antagonist activities in animal and humans. SPRMs inhibit endometrial proliferation and induce amenorrhea in non-human primates and humans. To evaluate the effects of asoprisnil, J912, and J956 on weights and morphology of the uterus and vagina in intact and ovariectomized (OVX) guinea pigs. The effects of SPRMs were compared with those of promegestone (R5020, pure progestin), progesterone (P) and the antiprogestins mifepristone (RU486) and onapristone (ONA). Intact guinea pigs (n=5/group) were treated subcutaneously (s.c.) with either the SPRMs or the reference compounds RU486, ONA, R5020, P or vehicle from cycle day 8–14 (dose/animal/day: 1.0mg for promegestone and 10.0mg for the other compounds). OVX guinea pigs (n=7/group) were primed s.c. with estradiol (E2) (0.03μg/day for 5 days) and then treated with the SPRMs and the reference compounds for 14 days in the presence of E2 (same dose). Autopsy was performed 24 hours later. Histological evaluation was based on serial HE-stained paraffin sections (6–10μm). SPRMs, progesterone and R5020, but not the antiprogestins, significantly (p<0.05) reduced the uterine and vaginal weights in intact animals. Proliferation and cornification of the vaginal epithelium prevailed after ONA and RU486. The employed E2 dose, when administered alone, led to minor increase of uterine and vaginal weights. ONA enhanced E2 effects on the uterus and vagina. Vaginal and endometrial histology revealed a massive epithelial proliferation, consistent with an “unopposed” estrogenic effect. The endometrium of animals exposed to ONA+E2 was highly hyperplastic with cystic changes. In contrast, the SPRMs and R5020 restored secretory appearance of the endometrium and induced mucification of the vaginal epithelium. Asoprisnil and the structurally related SPRMs exhibited P agonist effects on endometrial and vaginal morphology in both intact and OVX guinea pigs. In contrast, the antiprogestins induced a condition of “unopposed” estrogenic effects in the vagina and uterus. Asoprisnil has the potential to control hormone-dependent gynaecological disorders without inducing “unopposed” estrogen effects.