Antiestrogen compounds exhibit a variety of different effects in different tissues and are widely used for the treatment of osteoporosis, breast cancer, and other diseases. Upon examining the molecular mechanisms, we found that Smad4, a common signal transducer in the bone morphogenetic protein (BMP)/transforming growth factor-␤ (TGF-␤) signaling pathway, functions as a transcription corepressor for human estrogen receptor ␣ (ER␣). Endogenous ER␣ was co-immunoprecipitated with Smad4, and the interaction was induced by antiestrogen ligands such as tamoxifen, raloxifene, and droloxifen, which was confirmed in chromatin immunoprecipitation assays. Smad4 and ER␣ form a complex when ER␣ binds to the estrogen-responsive element within the estrogen target gene promoter. Importantly, the expression of Smad4 inhibits both antiestrogeninduced luciferase activity and estrogen downstream target gene transcription in breast cancer cells. Mapping of the interaction domains indicates that the activation function 1 (AF1) domain of ER␣ is essential for its interaction with Smad4, while the MH1 domain and linker region of Smad4 are essential for the interaction. Our findings represent a novel mechanism that TGF-␤ may regulate cell fate through Smad4-mediated crosstalk with estrogen.