The tumor promoter and irritant, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), previously shown to be a potent histamine releaser, has been used to further probe the mechanism of histamine release from human basophils. TPA and the calcium ionophore, A23187, produced a synergistic response in which subeffective concentrations of each stimulus (which alone produced less than 3% release) together produced over 70% histamine release. TPA also synergized with the IgE cross-linking stimulus anti-IgE. Desensitization of cells by incubation with anti-IgE in the absence of calcium rendered the cells unresponsive to anti-IgE and super-responsive to TPA. This marked increase in the TPA response was the result of an increase in the rate of TPA-induced histamine release, and occurred in the absence of extracellular calcium. The ability of various concentrations of anti-IgE to "sensitize" cells to TPA paralleled their ability to produce histamine release in untreated cells rather than their ability to desensitize the cells. These results suggest that in the absence of calcium, anti-IgE induces desensitization of some activation of other elements of the histamine-release process. The anti-IgE dose-response pattern of this activation event further suggests that it is an integral part of the anti-IgE-induced release process itself.