The 'pure' antiestrogen ICI 182,780 (Faslodex) is in clinical trials for treatment of human breast cancer. Recently, we showed that ICI 182,780 exhibits a novel antiprogestin activity in transient transfection assays in the total absence of estrogen receptors. In this work, we determined if ICI 182,780 displays antiprogestin activity for an endogenous progesterone responsive gene. For this purpose, we examined the effect of ICI 182,780 on progestin induction of a potent angiogenic growth factor, vascular endothelial growth factor (VEGF), in T47-D human breast cancer cells. ICI 182,780 blocks the progestin induction of VEGF at both the mRNA and protein levels in T47-D cells. The antihormone does not block progestin binding to the progesterone receptor (PR), nor does it enhance the down regulation of the endogenous PR in cells that occurs upon progestin exposure. These results establish that ICI 182,780, generally considered to be a highly selective antiestrogen, displays antiprogestin activity for an endogenous progestin-regulated gene. These observations raise the possibility that an antiprogestin activity of ICI 182,780 may contribute to the antitumor activity in a subset of human breast cancers similar to T47-D cells, by inhibiting angiogenesis secondary to blockade of VEGF induction.