Dietary soy intake is associated with protection from breast cancer, but questions persist on the potential risks of the major soy isoflavone genistein (GEN) on female reproductive health. Here, we evaluated intermediate markers of cancer risk in uteri of cycling, young adult Sprague-Dawley rats lifetime exposed to one of three AIN-93G semipurified diets: casein (CAS), soy protein isolate (SPI+ with 276 mg GEN aglycone equivalents/kg) and CAS+GEN (GEN at 250 mg/kg). Postnatal day 50 (PND50) rats lifetime exposed to GEN or SPI+ had similar uterine luminal epithelium height, myometrial thickness, endometrial gland numbers, endometrial immunoreactive proliferating cell nuclear antigen (PCNA), and serum estrogen and progesterone, as CAS-fed rats. GEN-fed rats showed modestly increased apoptosis in uterine glandular epithelium, compared to those of CAS- or SPI+-fed groups. Diet had no effect on the uterine expression of genes for the tumor suppressors PTEN, p53 and p21, and the apoptotic-associated proteins Bcl2, Bax and progesterone receptor. Uterine tissue and serum concentrations of total GEN were higher in rats fed GEN than in those fed SPI+. Human Ishikawa endocarcinoma cells treated with GEN-fed rat serum tended to exhibit increased apoptotic status than those treated with CAS-fed rat serum. Exogenously added GEN (0.2 and 2 microM) increased, while estradiol-17beta (0.1 microM) decreased Ishikawa cell apoptosis, relative to untreated cells. Results suggest that lifetime dietary exposure to soy foods does not alter uterine cell phenotype in young adult rats, while GEN, by enhancing uterine endometrial glandular apoptosis in vivo and in vitro, may confer protection against uterine carcinoma. Given its limited influence on uterine phenotype of young adult females, GEN, when taken as part of soy foods or as supplement, should be favorably considered for other potential health benefits.