Selective estrogen receptor modulators (SERMs) have tissue-specific estrogen receptor (ER) modulating properties. Combining an SERM with one or more estrogens to form a tissue selective estrogen complex (TSEC) can provide an improved blend of tissue-specific ER agonist and antagonist effects. While both estrogens and SERMs affect the uterine endometrium, not all TSECs reverse the endometrial effects of estrogens preventing endometrial proliferation and hyperplasia. Their action in uterine cells is not completely understood. HOXA 10, leukemia inhibitory factor (LIF), progesterone receptor (PR), and EMX2 are genes known to regulate endometrial proliferation and differentiation. The expression of these genes was used to assess endometrial effects of SERMs and TSECs. We evaluated the effects of raloxifene (RAL), tamoxifen (TAM), lasofoxifene (LAS), bazedoxifene acetate (BZA), and progesterone (P) alone and in combination with estradiol (E2) in Ishikawa cells. Increased HOXA10, LIF, PR, and EMX2 messenger RNA (mRNA) expression was noted in E2-treated cells compared with vehicle-treated controls. All TSECs maintained E2-induced PR expression and all except TAM prevented estrogen-induced LIF expression. The TSEC containing BZA uniquely decreased HOXA10 expression and increased EMX2 expression. The TSECs alter endometrial cell proliferation by selective modulation of estrogen responsive genes, maintaining the antiproliferative effects mediated by PR and inhibiting LIF. The differential effect of TSECs on endometrial gene expression suggests a mechanism by which they manifest differential effects on endometrial safety against the risk of estrogen-induced endometrial hyperplasia.