Finding contact sensitivity (CS) responses that were fairly normal in ear swelling, and in serotonin (5-HT) dependence in mast-cell-deficient mice, led to experiments to determine whether platelets supplemented mast cells as a source of 5-HT in CS. Severe depletion of platelets, and consequently blood 5-HT, with antiplatelet antibody, strongly inhibited CS, especially in mast-cell-deficient mice, suggesting that platelets supplemented mast cells. Furthermore, human platelets sensitized in vitro with anti-(tri-nitro-phenyl) IgE, and transferred intravenously together with isolated late-acting effector T cells, provided CS initiation due to local 5-HT release. Similar, IgE-dependent in vitro release of 5-HT was C dependent. These findings establish the importance of antigen-specific platelet release of 5-HT in CS initiation.