We report that gp49B1, a mast cell membrane receptor with two immunoreceptor tyrosine‐based inhibitory motifs (ITIM), constitutively inhibits mast cell activation‐secretion induced by stem cell factor (SCF), a tissue‐derived cytokine that also regulates mast cell development. The intradermal injection of SCF into the ears of gp49B1 null (gp49B^–/–) mice elicited∼4‐ and 2.5‐fold more degranulating mast cells and tissue swelling caused by edema, respectively, than in gp49B^+/+ mice. SCF did not induce tissue swelling in mast cell‐deficient mice, and the responsiveness of gp49B^–/– mice to mast cell‐associated amine and lipid mediators was unaltered. When gp49B^+/+ and gp49B^–/– mice were pretreated with antagonists of the amines, SCF‐induced tissue swelling was reduced by >90% and 60%, respectively, and it was reduced by >90% in both genotypes when a cysteinyl leukotriene receptor antagonist was also provided. Hence, the dominant contribution of secretory granule amines to SCF‐induced tissue swelling is the result of gp49B1‐mediated inhibition of the production of cysteinyl leukotrienes by mast cells. Our findings also provide the first example of an ITIM‐bearing receptor that constitutively suppresses inflammation generated in vivo independently of the adaptive immune response by a receptor that signals through intrinsic tyrosine kinase activity rather than immunoreceptor tyrosine‐based activation motifs.