Bisphenol A(BPA) is one of the most widespread endocrine disruptors in the environment and is associated with reproductive diseases. In this study, we focused on the correlation between environmentally relevant levels of BPA exposure and histone modification during endometrial stromal cells decidualization. BPA exposure changed the morphology of decidualized endometrial stromal cells, with inhibition of mixed-lineage leukemia 1(MLL1) and induction of enhancer of zeste homolog2 (EZH2) during in vitro decidualization. The expression of HOXA10, PRL and IGFBP-1 was down-regulated upon BPA treatment. Furthermore, chromatin immunoprecipitation quantitative PCR(ChIP-qPCR) was performed to evaluate the recruitment of histone-3, lysine-4 trimethylation (H3K4me3) and histone-3, lysine-27 trimethylation (H3K27me3) at the gene promoters. The decreased H3K4me3 and the increased H3K27me3 at HOXA10, PRL and IGFBP-1 promoter regions were consistent with the expression of MLL1 and EZH2 respectively. The effect of BPA on MLL1 and EZH2 could be abrogated by ICI 182,780. Our study provides the first indication that environmentally relevant levels of BPA exposure can regulate the expression of decidualization-related genes by affecting histone modification, impairing endometrial decidualization.