The cells involved in allergic inflammation, such as mast cells, basophils, and eosinophils, have been thoroughly studied in the nose, the lungs and the skin, demonstrating an evident increase in response to the introduction of the specific allergen, while little is known in the mucosal system and particularly in the oral mucosa. We investigated such tissue by using the model of sublingual immunotherapy (SLIT), by which high doses of the specific allergen enter the mouth. Oral biopsies were carried out on seven subjects allergic to grass pollen and treated with SLIT by a grass extract. In biopsies carried out before SLIT there was a very low number of mast cells and eosinophils both in the epithelium and subepithelium layers, and insignificant changes were detected after SLIT. These findings show the lack of allergic inflammation in the oral mucosa upon contact with the specific allergen and confirm the role of the mouth as a tolerogenic site, which is conceivable considering the different attitude of the mouth, where the antigens transit to undergo digestion, in respect to the airways or the skin, where the antigen absorption is potentially dangerous.