Background: There is need for a fast, efficient, and safe way to induce tolerance in patients with allergic rhinitis. Methods: Patients with 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. 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. Nine patients had severe adverse events which were judged to be unrelated to the therapy. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased independently of treatment. 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 effective, safe and associated with bystander immune modulatory responses.