The present study aimed at improving our understanding of the effects of 17beta-estradiol and phytoestrogens on the uterine tissue, by evaluating tissue-specific modulation of molecules related to cell-cycle control and angiogenesis. Specifically, the uterine expression of Ki67, peroxisome proliferator-activated receptor gamma (PPARgamma), and vascular endothelial growth factor receptor-2 (VEGFR-2), was examined by immunohistochemical analysis. Ovariectomized (OVX) rats were treated with either the vehicle, a phytoestrogen- containing soy extract (SSE) (100 mg/kg/day pos), or 17beta-estradiol (0.5 mg/kg/day pos); a sham control group (SHAM) was also included in the study. At necropsy, uteri were weighed, collected, and subsequently processed for histopathology or immunohistochemistry. SSE-treated rats did not show any significant change either in the weight or in histological features of the uterus when compared to OVX controls; the epithelial expression of proliferation marker Ki67 was seen to be significantly reduced, in comparison to both SHAM and OVX rats. Conversely, 17beta-estradiol significantly increased uterine weight, induced hyperplasia in the majority of rats, and enhanced Ki67 epithelial expression. The regulation of PPARgamma expression, reduced after ovariectomy, was similar in SSE- and 17beta-estradiol-treated rats, showing a further significant decrease in stromal immunostaining, in comparison to OVX controls. VEGFR-2 epithelial immunostaining, slightly reduced following ovariectomy, was highly increased on 17beta-estradiol treatment, while following SSE, the pattern of staining observed was similar to that of OVX controls. Data from this study show that PPARgamma and VEGFR-2 represent additional targets by which sex steroid estrogen and plant-derived phytoestrogens may, at certain doses, differentially regulate endometrial functions.