Abstract IgE/FcεRI-mediated mast cell and basophil activation has a central role in food allergy and drug allergy. Although desensitization therapy can suppress these disorders, it can be complicated by anaphylaxis. Pre-treatment with antihistamines and other mediator antagonists can increase the safety of desensitization, but is not completely effective. Because the tyrosine kinase Syk has an important role in FcεRI-dependent mast cell activation and the tyrosine kinase Kit is critical for mast cell survival, we evaluated whether treating mice systemically with a combination of an antihistamine (triprolidine, 200 µg), the Syk inhibitor fostamatinib (80 mg/kg), and the c-Abl/c-Kit inhibitor, imatinib mesylate (1.25 mg), 30 min prior to challenging them intravenously with an anti-IgE mAb, would prevent development of anaphylaxis (measured by hypothermia); mast cell degranulation (measured by increases in serum MMCP1); and/or basophil activation (measured by increases in IL-4 secretion). Pretreatment with this 3-agent cocktail completely suppressed hypothermia and decreased MMCP1 by >80%, but had little effect on IL-4 secretion. Triprolidine and fostamatinib independently partially suppressed hypothermia and fostamatinib, by itself, suppressed MMCP1 by 50-60%. No obvious drug toxicity was noted. These results suggest the possibility of using a combination of mediator and tyrosine kinase antagonists to increase the safety of rapid and conventional desensitization therapy.