Background: Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed. Objective: To investigate the clinical efficacy of SLIT vs SCIT and secondary to compare SLIT and SCIT with placebo and to evaluate the relative clinical efficacy in relation to systemic side effects. Methods: A 3-year randomized, placebo-controlled, double-blind, double-dummy study including 71 adult birch pollen, hay fever patients treated for two consecutive years after a baseline year. Allocation to treatment groups was based on disease severity in the baseline season, gender and age. Results: Clinical efficacy was estimated in 58 patients completing the first treatment year by subtracting baseline data, and by calculating the ratio first treatment season vs baseline. SLIT diminished the median disease severity to one half and SCIT to one-third of placebo treatment. No statistically significant difference between the two groups was observed. Both for symptoms and medication scores, actively treated patients showed statistically significant and clinically relevant efficacy compared with placebo. SLIT treatment only resulted in local mild side-effects, while SCIT resulted in few serious systemic side-effects. Conclusion: Based on the limited number of patients, the clinical efficacy of SLIT was not statistically different from SCIT, and both treatments are clinically effective compared with placebo in the treatment of birch pollen rhinoconjunctivitis. The lack of significant difference between the two treatments does not indicate equivalent efficacy, but to detect minor differences necessitates investigation of larger groups. Due to the advantageous safety profile, SLIT may be favored.