To investigate the possible role of mast cells in blood vessel formation, rat mast cell granules were studied for their proliferative effect on human microvascular endothelial cells. It was found that granules had a marked proliferative effect and that most of this activity was restricted to a dialyzable fraction. The dialyzable mast cell granule constituent histamine was found to be mitogenic, an effect that was shown with the use of specific agonists and antagonists to be mediated through an H1 receptor. H1 antagonists reduced the proliferation caused by the untreated mast cell granules to the level of proliferation caused by dialyzed granules, suggesting that all the dialyzable mitogenic activity was due to histamine. Histamine was also shown to cause proliferation of cells that were growth arrested by serum deprivation, suggesting that it is an endothelial growth factor. The compound responsible for the undialyzable mitogenic activity could not be identified but was shown not to be mast cell heparin. This demonstration of mast cell granule-induced endothelial proliferation suggests that the mast cell may be of importance in the process of angiogenesis.