Embryo implantation requires a precise synchronism between the receptive uterus and activated blastocyst, and is regulated by complicated molecular networks. Although many implantation-related genes have been identified, the interaction among them is still unknown. In this study, we first showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF)-soaked beads can induce Snail expression in the subluminal stroma at implantation site of mouse uterus. In the cultured stromal cells, Snail is also stimulated by HB-EGF. By using specific inhibitors and siRNA, we demonstrated that HB-EGF induction on Snail expression is mediated through EGFR, PI3K/Akt and MEK/ERK, and Stat3 pathway. In addition, we verified that Cox-2 is transcriptionally regulated by Snail. In cultured uterine stromal cells from mouse and human, in vitro decidualization causes the down-regulation of Snail expression and up-regulation of E-cadherin expression, during which stromal cells lose elongated shape and show epithelium-like characteristics. Our findings suggest that Snail may play a key role during mouse decidualization through the crosstalk with HB-EGF, Stat3 and Cox-2.