Background: Mast cells are known for their role in allergy, asthma, and systemic anaphylaxis, and have been shown to play a role in inflammatory disease. Interleukin-10 can regulate inflammatory responses both in vitro and in vivo, and may be a natural regulator of mast cell activation.Objective: To examine Interleukin-10 mediated regulation of FcεRI expression and related downstream signaling molecules, and to determine how this affects mast cell function in vitro and in vivo.Methods: Mast cell FcεRI expression was evaluated with and without IL-10 treatment in human lung and skin mast cells, and on peritoneal mast cells from mice overexpressing IL-10 via injection or a transgenic model. Mast cell function was evaluated by observing responses of IL-10 treated mice to passive systemic anaphylaxis.Results: Interleukin-10 inhibited FcεRI expression on mouse and human mast cells, both in vitro and in vivo. IL-10 also suppressed expression of the key signaling molecules Syk, Fyn, Akt and Stat5. Mice chronically overexpressing IL-10 had a reduced response to passive systemic anaphylaxis, indicating impaired mast cell activation.Conclusion: Interleukin-10 suppresses mast cell FcεRI expression in vitro and in vivo, and reduces IgE-mediated activation. The anti-inflammatory effects of IL-10 may relate to its suppression of critical signaling molecules.Clinical Implications: Interleukin-10 polymorphism is associated with increased IgE levels and incidence of atopic disease; hence IL-10 dysregulation may affect atopic etiology. Further, IL-10 therapy is a possible treatment for atopic allergy and asthma.