Resistance to tamoxifen treatment occurs in approximately 50% of the ER positive breast cancer patients. Resistant patients would benefit from treatment with other available anti-estrogens. Arzoxifene is an effective growth inhibitor of ER positive breast cancer cells, including tamoxifen resistant tumors. In this study, we show that overexpression of a regular component of the ER transcription factor complex, cyclin D1, which occurs in approximately 40% of breast cancer patients, renders cells resistant to a new promising anti-estrogen arzoxifene. Overexpression of cyclin D1 alters the conformation of ER in the presence of arzoxifene. In this altered conformation, ER still recruits RNA polymerase II to an ERE-containing promoter, inducing transcription of an ER-dependent reporter gene and of endogenous pS2, and promoting arzoxifene-stimulated growth of MCF-7 cells. Arzoxifene is then converted from an ER-antagonist into an agonist. This can be explained by a stabilization of the ER/SRC-1 complex in the presence of arzoxifene, only when cyclin D1 is overexpressed. These results indicate that subtle changes in the conformation of ER upon binding to anti-estrogen are at the basis of resistance to anti-estrogens.