Sublingual administration of a protein allergen to immunologically naïve rats suppressed subsequent allergen-specific IgE responses. Susceptibility to this form of immunotherapy was genetically determined, with some inbred rat strains displaying immunological tolerance in the IgE antibody class alone, whilst others developed concomitant suppression of IgG. Parallel gastric intubation experiments established that the development of tolerance by sublingual allergen administration proceeded independently of events occurring in the gut resulting from swallowing the allergen. These results are consistent with clinical reports which suggest that the oral mucosa is a potentially useful site for therapeutic modulation of allergic reactivity, and indicate that appropriate animal models can be developed to probe this important question. However, further research is required to determine the relevance of these findings to current sublingual desensitization practices.