Mast cells elicit allergic reaction through degranulation and release of proinflammatory mediators after aggregation of the IgE receptor FcεRI. Here we provide evidence to show that signal regulatory protein α (SIRPα), an ITIM-containing receptor, is an endogenous regulator of IgE-Ag induced mast-cell activation. SIRPα expression is promptly reduced in mast cells in response to FcεRI aggregation. Impaired expression of SIRPα in mast cells facilitates FcεRI-evoked degranulation and de novo synthesis of cytokines (IL-4, IL-13, IL-6, and TNF-α). We further demonstrate that SIRPα knockdown in mast cells accelerates calcium mobilization and affects cytoskeletal rearrangement (F-actin disassembly and polymeric tubulin formation) after FcεRI aggregation. Mechanistic studies highlight the prolonged activation of NF-κB and MAPKs as well as PLC-γ after FcεRI stimulation as a consequence of the inhibition of SIRPα expression in mast cells. Immunoprecipitation analysis shows that SIRPα knockdown markedly increases IgE-induced SHP2 interaction with PI3K regulatory subunit PI3Kp85 or IKK-β in mast cells, indicating that SIRPα may accomplish this through its association and sequestration of SHP2. Collectively, our results strongly indicate that SIRPα is a biological important regulator of FcεRI signaling.