Interepithelial cells are found in all epithelia of the internal and external surfaces of the mammalian body. The regional differences of these interepithelial cells and their function are not completely known so far. The quantitative and qualitative changes of the interepithelial cell population were investigated in germfree, specific pathogen-free and conventionalized mice by light and electron microscopy. Germfree and specific pathogen-free animals did not show significant differences in the number of interepithelial cells. In the epithelium of the tongue a mean of 7.4 cells per 1000 basal cells is found. After conventionalization a significant increase to 14.4 interepithelial cells per 1000 basal cells is observed. The number of cells in the buccal epithelium is constantly about 20% higher than in the epithelium of the tongue. In the oral mucosa lymphocytes, cerebriform cells and Langerhans cells are an integral component of the epithelium. In contrast to the monostratified intestinal mucosal epithelium, which is considered a secondary lymphatic tissue, the interepithelial lymphocytes of the oral mucosa are not significantly decreased in germfree animals. This could indicate that the oral mucosa functions partly as a primary lymphatic tissue. Interepithelial cerebriform cells and Langerhans cells increased after conventionalization with a maximum after 10 days in response to exogenous antigens. Both cells are immunologically important. The observations prove that the oral mucosa represents a local immunologic system in which the Langerhans cells plays an important part by formation a reticulo-epithelial tissue.