Background: There is need for a fast, efficient, and safe way to induce tolerance in patients with severe allergic rhinitis.Methods: Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. We have no clean placebo group but the pollen seasons are mostly divided by time. Rhinoconjunctivitis Total Symptom Score, Medication Score and Rhinoconjunctivitis Quality of Life Questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analyzed by flow cytometry and Luminex.Results: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased three years after treatment.Conclusion: Intralymphatic immunotherapy against grass and birch pollen allergy was safe, seemed to be effective, and to be associated with bystander immune modulatory responses.Trial registration: EudraCT (2013-004726-28). Registered 14 January 2014https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004726-28