Arzoxifene (ARZ) is a selective estrogen receptor (ER) modulator with greater bioavailability than raloxifene which is being developed as treatment for breast cancer. We have used an in vivo model of hormone-sensitive breast cancer to study the growth-inhibitory and pharmacodynamic effects of ARZ in comparison with the most widely used antiestrogen, tamoxifen (TAM). We compared the abilities of ARZ and TAM to antagonize the estrogen (E2)-dependent growth of MCF-7 human breast cancer xenografts in oophorectomized athymic mice. At four different time points over 28 days, we studied their time-related pharmacodynamic effects on biomarkers of tumor growth (cell proliferation/death measured by Ki-67 and apoptosis scores), cell cycle activity (cyclin D1 and p27(kip1)), and hormone-regulated gene expression (ERalpha, progesterone receptor, and pS2). Although maximal growth inhibition was seen after E2 withdrawal, ARZ and TAM induced significant and similar inhibition of E2-stimulated tumor growth. Inhibition of growth was reflected by changes in the tumor growth index (ratio posttreatment/pretreatment Ki-67/apoptosis scores). ARZ and TAM resulted in a significant (P < 0.001) increase in ER expression and reduction in progesterone receptor expression, whereas changes in cyclin D1 score were inversely related to p27(kip1) score. A significant but delayed biological effect was observed with a 10-fold lower dose of ARZ. These results show that ARZ is an effective antagonist of E2-stimulated breast cancer growth with similar growth-inhibitory and pharmacodynamic effects to TAM in this model.