Background: Sublingual immunotherapy (SLIT) is a safe and effective treatment for allergic diseases. While it is generally accepted that SLIT-induced tolerance is allergen-specific, it has been suggested that SLIT may also prevent the development of new sensitizations or even confer protection towards unrelated allergens. Methods: In the present study we applied murine models of systemic sensitization to investigate allergen-specific as well as bystander tolerance induced by SLIT. Results: We demonstrate that prophylactic SLIT with Phleum pratense (Phl p) extract leads to allergen-specific systemic tolerance in mice and that this tolerance is more efficiently induced via the sublingual route compared to the peroral and intranasal routes. In addition to antigen-specific tolerance, SLIT with Phl p extract also induced bystander tolerance, as demonstrated by downregulated reactivity towards the unrelated protein ovalbumin (OVA). Bystander tolerance was dependent on the presence of Phl p extract during OVA sensitization, indicating that co-exposure is critical for the effect. Finally, by assessing the ability of different antigens (allergens as well as non-allergens) to induce bystander tolerance, we observed that the ability to induce bystander tolerance correlated with the immunogenicity of a given protein. Conclusion: Prophylactic SLIT with immunogenic proteins is able to prevent the spred of sensitizations to other antigens. This supports that allergy immunotherapy, used as primary prevention, may prevent development of new sensitizations to additional allergens and thereby influence the allergic march.