There is strong evidence that decreased pregnancy rates and higher miscarriage rates exist in obese women. Whether these effects are secondary to abnormal implantation, embryo development, or poor oocyte quality are unknown, although all of these factors may contribute. Our study objective was to investigate, via an in vivo and in vitro model, whether exposure of endometrial stromal cells (ESC) to saturated fatty acids or a high fat environment impairs decidualization. To test the effects of diet-induced obesity on ESC decidualization in vivo, artificial deciduomas were induced in high fat-fed versus chow-fed control mice. In vitro cell culture models were also used to determine the impact of saturated fatty acids on ESC differentiation. Artificial Deciduoma: Six-week old C57BL/6 female were fed either a high fat diet (59.4% Kcal from fat, HFD) or chow (CON) for twelve weeks. To induce decidualization in vivo, a silk thread was placed in the left uterine horn of pseudopregnant CON (n=5) and HFD (n=6) mice on dpc 3.5. Three days after thread placement, uterine horns were collected, and deciduoma formation was evaluated by comparing the uterine masses and morphologic changes via histology. In Vitro Decidualization: Human immortalized endometrial stromal cells (hESC-T) and human primary endometrial stromal cells were cultured in 1μM medroxyprogesterone-17-acetate and 0.5mM dibutyryladenosine cAMP for 9 days to induce decidualization. During this time, cells were also treated with either saturated fatty acids (100μM palmitic acid ) or vehicle (BSA). RNA was isolated and RT-qPCR was performed to analyze expression of decidual markers, IGFBP1 and PRL. HFD mice were significantly heavier, had 100% increase in fat mass, and were glucose intolerant. Furthermore, we observed a 36% decrease in deciduoma weights and impaired ESC differentiation via histological analysis in the HFD vs. CON mice. In vitro studies also revealed that hESC-T cells differentiated in the presence of saturated fatty acids had significantly lower gene expression of IGFBP-1 and PRL, indicating impaired decidualization. This observation was confirmed in human primary endometrial stromal cells. Taken together, these data indicate that a diet high in saturated fatty acids may impair uterine receptivity via altered ESC decidualization. Although the mechanism by which this occurs needs to be further investigated, our preliminary data suggests that poor decidualization may contribute to implantation defects in obesity.