The influence of exogenous addition of gangliosides on histamine release from human basophils and rat mast cells was examined in vitro. Gangliosides dose-dependently inhibited histamine release, and this inhibition was dependent on the ganglioside sialic acid content, since GT1b, having 3 sialic acid moieties, was more potent than gangliosides with 2 moieties (GD1a and GD1b), which again were more potent inhibitors than GM1 with one moiety. Asialo-GM1 was without effect. In high concentrations the gangliosides potentiated basophil histamine release. The modulation of histamine release was reflected in the sensitivity of the cells to extracellular calcium, since inhibition of the release could be counteracted by increasing the extracellular concentration of calcium.