Vascular endothelial growth factor (VEGF) is considered a key mediator of tumor angiogenesis, including neovascularization in human breast cancer. High tissue VEGF levels appear to correlate with poor prognosis and decreased overall survival in node-positive and node-negative breast cancer patients. Hormonal regulation of VEGF expression has been demonstrated, and some reports indicate that tamoxifen, a partial estrogen receptor agonist, increases VEGF mRNA in breast cancer cells. These results appear to contradict the efficacy of tamoxifen as an adjuvant for estrogen-dependent breast cancer, yet clinical data show that tamoxifen prevents metastasis and increases overall survival. In this study, we confirmed previous studies showing that intracellular levels of VEGF in vitro increased in response to tamoxifen to levels similar to those observed after estrogen treatment. To further study hormonal effects on the release of VEGF, we used microdialysis to sample the extracellular space, where VEGF is biologically active, in solid tumors in situ. We show for the first time that tamoxifen decreased extracellular VEGF in vivo in solid MCF-7 tumors in nude mice. These in vivo findings were confirmed in vitro where extracellular VEGF in the cell culture medium was decreased significantly by tamoxifen treatment. Furthermore, we illustrate that microdialysis is a viable method that may be applied in human breast tissue to detect soluble VEGF in situ released by the tumor.