The specific activation of mast cells in situ causes vigorous local mast-cell mediated angiogenesis (MCMA). The mast cell is a major source of histamine and, as recently reported, specific histamine H1- and H2-membrane receptor antagonists are able individually to significantly suppress MCMA in rats, as assessed using the mesenteric window angiogenesis assay (MWAA). In addition to membrane receptors for histamine, a type of intracellular histamine receptors, designated Hic, has been described. It is now demonstrated that the potent Hic-receptor antagonist DPPE (N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl), administered parenterally, stimulates MCMA significantly in rats, as quantified by the MWAA. Although the target cell(s) are not known, there are several ways by which their Hic receptors could be activated: uptake of histamine released from mast cells, mobilization from preformed cytoplasmic and nuclear stores, and production of de novo histamine by histidine decarboxylase activity. The fact that the occupancy by histamine of H1- and H2-membrane receptors stimulates MCMA and the occupancy by histamine of Hic inhibits MCMA suggests that endogenous histamine is capable of regulating angiogenesis by a dual mode of action. This is apparently the first report ascribing a dual role of this type in angiogenesis to a single molecule.