Background: DJ-1 is an antioxidant protein known to reduce levels of reactive oxygen species (ROS), but its presence or function in mast cells and allergic diseases is unknown. Objectives: We sought to determine the role and mechanism of DJ-1 in allergic responses in vitro and in vivo. Methods: ROS and DJ-1 levels in serum or culture medium were measured with ELISA kits. The role of DJ-1 was evaluated in mast cell cultures and passive cutaneous anaphylaxis in normal or DJ-1 knockout (KO) mice. The mechanism of DJ-1 action was examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biological approaches. Results: Patients with atopic dermatitis had increased levels of ROS and diminished levels of DJ-1. DJ-1 KO mice exhibited enhanced passive cutaneous anaphylaxis and augmented ROS levels in sera and bone marrow�derived mast cells (BMMCs). Furthermore, antigen-induced degranulation and production of TNF-? and IL-4 were significantly amplified in DJ-1 KO and anti�DJ-1 small interfering RNA�transfected BMMCs compared with that seen in wild-type (WT) BMMCs. Studies with these cells and BMMCs transfected with small interfering RNAs against the phosphatases Src homology domain 2-containing protein tyrosine phosphatase (SHP) 1 and SHP-2 revealed that the DJ-1 KO phenotype could be attributed to suppression of SHP-1 activity and enhancement of SHP-2 activity, leading to strengthened signaling through linker for activation of T cells, phospholipase C?, and mitogen-activated protein kinases. Conclusions: A deficiency or constitutive activation of DJ-1 can have implications in mast cell�driven allergic diseases, such as asthma and anaphylaxis.