Background nicotine adversely affects the female reproductive system and changes the methylation pattern of some genes in the placenta. In contrast, caffeic acid phenylethyl ester) CAPE (, as a potent antioxidant, has protective effects against the harmful effects of oxygen free radical molecules, methotrexate, and pesticides on the reproductive system. To find the effect of nicotine on the endometrium, we investigated three markers of endometrium receptivity including fibroblast growth factor 2, vascular endothelial growth factors A, and C-X-C motif chemokine ligand 12 and also changes in methylation levels of CXCL-12 gene promoter. In addition, we evaluated the protective effect of CAPE against nicotine. Methods the appropriate treatment dose was selected based on the literature, the endometrial stromal cells were divided into 4 groups, including control, treated with nicotine, CAPE, and nicotine followed by CAPE. Finally, the quantitative polymerase chain reaction and Methylation-Specific PCR were carried out. Results The results showed that treatment of endometrial stromal cells with nicotine (10− 6 µM) for 24 h significantly reduced expression of CXCL-12, FGF, and VEGFA genes. However, a decrease in CXCL-12 expression was not associated with increased methylation levels in the studied promoter region. In contrast, endometrial stromal cells treated with CAPE (4 µg/ml) for 24 h adverse significantly nicotine-induced reduction of CXCL-12, FGF, and VEGFA genes expression. Conclusion Exposure to nicotine has negative effects on uterine receptivity, implantation, and fertility, via reducing the expression of VEGFA, CXCL-12, and FGF2 genes. In contrast, CAPE has a protective effects and improves these genes expression.