During oral infection, mucosal immunity assumes a predominant role. Here, we addressed the role of mast cells (MCs), which are mainly located in mucosa during oral infection with Toxoplasma gondii, using MC-deficient (W/Wv) mice. We show that in the absence of MCs the resistance of W/Wv mice to oral infection was considerably reduced. W/Wv mice uniformly succumbed within 15 days of infection after administration of cysts of the ME49 strain of T. gondii. The rapid lethality of T. gondii in W/Wv mice correlated with a delayed Th1-cell response, since IFN-γ and IL-12 levels peaked in the later phase of the infection. In vitro, bone marrow-derived MCs (BMMCs) were able to recognize parasite lysate in a MyD88-dependent way, reaffirming the role of this TLR adapter in immune responses to T. gondii. The importance of MCs in vivo was confirmed when W/Wv mice reconstituted with BMMCs derived from control mice retrieved an early strong Th1-cell response and specially a significant IL-12 production. In conclusion, mast cells play an important role for the development of a protective immune response during oral infection with T. gondii.This article is protected by copyright. All rights reserved