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Background In addition to their well-known role as potent effector cells in patients with allergic disease, mast cells have important immunomodulatory roles regulating tolerance in allograft rejection models. The roles of mast cells in oral tolerance development have not previously been examined. Objective We sought to evaluate the importance of mast cells, IgE-mediated mast cell activation, and histamine receptor 1 or 2 blockade on oral tolerance development in mice. Methods Oral tolerance was assessed in 2 mast cell–deficient murine strains ( Kit W-sh/W-sh and Kit W/W-v mice) and control mice. Mice were fed ovalbumin (OVA) or peanut butter for 1 week and then immunized and boosted with relevant protein antigens. Antibody responses were assessed by using ELISA. The oral antihistamines pyrilamine and ranitidine were administered during tolerance induction to OVA. IgE-mediated mast cell activation was initiated during oral tolerance induction or OVA immunization. OVA-specific regulatory T cells were assessed in the Peyer patches, mesenteric lymph nodes, and spleens by using flow cytometry after adoptive transfer. Results Oral tolerance was successfully induced to OVA and peanut butter in mast cell–deficient mice. Kit W-sh/W-sh mice had higher proportions of antigen-specific regulatory T cells in the mesenteric lymph nodes than mast cell–containing control mice. However, mast cell reconstitution studies suggested this effect was mast cell independent. Oral antihistamine treatments with pyrilamine or ranitidine did not impair tolerance and neither did IgE-mediated activation. Conclusions Mast cells are not necessary for the induction of oral tolerance, and allergic activation of mast cells does not impair tolerance to OVA. Oral antihistamine treatments do not disrupt the development of oral tolerance.