Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with the degree of vascularity, progression, and metastasis of breast cancer, and cases of this disease with increased vascular density have a poor prognosis. We show that in T47-D human breast cancer cells, progesterone induces a dose-dependent increase of 3-4-fold in media VEGF levels, with a maximum response occurring at a concentration of 10 nM. This effect is blocked by the antiprogestin RU 486. In addition to progesterone, a number of synthetic progestins used in oral contraceptives (e.g., norethindrone, norgestrel, and norethynodrel), hormone replacement therapy (medroxyprogesterone acetate), and high-dose progestin treatment of breast cancer (megestrol acetate) also increase VEGF in the media of cultured T47-D cells. This effect is hormone specific and is not produced by estrogens, androgens, or glucocorticoids. Collectively, these observations suggest that the increase in VEGF caused by progestins is mediated by progesterone receptors present in T47-D cells. The induction of VEGF by progestins is also cell type specific and does not occur in human breast cancer cell lines MCF-7, ZR-75, or MDA-MB-231, nor in Ishikawa cells derived from a human endometrial carcinoma. This is the first report that progestins regulate VEGF expression in human breast cancer cells and raises the possibility that increased angiogenesis in response to endogenous progesterone or its therapeutically used analogues may play a role in cell growth or metastasis in a subset of human breast tumors.