Potential mechanisms for tamoxifen resistance include loss or alteration in estrogen receptor or other transcription factors and altered tamoxifen pharmacology. Using an experimental model, we have previously demonstrated that one form of tamoxifen resistance is related to the acquired ability of tamoxifen to stimulate tumor growth. These tamoxifen-stimulated tumors contain a reduced tamoxifen concentration and an altered metabolite profile suggesting that accumulation of more estrogenic metabolites could explain this phenomenon. However, in vivo treatment of nude mice carrying tamoxifen-stimulated tumors with fixed ring non-isomerizable analogs, or other analogs resistant to conversion to metabolite E (a full estrogen), still resulted in tumor growth stimulation. Growth of these tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182,780, suggesting that this drug should be investigated in patients with tamoxifen resistance. These tamoxifen-stimulated tumors could be further stimulated by estrogen replenishment, and estrogen stimulation was blocked by tamoxifen, indicating that tamoxifen has both agonist and antagonist properties in these tumors. Our data suggest that although tamoxifen-stimulated tumors display a markedly altered metabolite profile, isomerization or metabolism of tamoxifen does not fully explain the development of tamoxifen-stimulated growth. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties over time remains to be defined.