We have previously reported that the partial estrogen antagonists, tamoxifen, clomiphene and nafoxidine, inhibited angiogenesis in vivo in a dose-related manner in the six-day old chick egg chorioallantoic membrane (CAM) assay. In the present study, we investigated the effect of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on the growth of porcine pulmonary artery and human dermal microvascular endothelial cells. Both of these growth factors significantly increased the growth of these cells. The antiproliferative activity of the partial antiestrogens, tamoxifen, nafoxidine and clomiphene, and the pure antiestrogen, ICI 182,780, was determined. Tamoxifen, clomiphene, nafoxidine and ICI 182,780 significantly inhibited endothelial cell growth stimulated by bFGF and VEGF. This inhibition of endothelial cells was not altered by the presence of up to 30 microM of estradiol-17 beta. These results indicate that the antiangiogenic action of the antiestrogens does not occur via the estrogen receptor, but by a direct inhibition of growth factor stimulated endothelial cell growth.