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Background We have developed a recombinant B cell epitope-based vaccine (BM32) for allergen-specific immunotherapy (AIT) of grass pollen allergy. The vaccine contains recombinant fusion proteins consisting of allergen-derived peptides and the hepatitis B surface protein domain preS as immunological carrier. Methods We conducted a randomized, double-blind, placebo-controlled AIT study to determine safety, clinical efficacy and immunological mechanism of three subcutaneous injections of three BM32 doses adsorbed to aluminum hydroxide versus aluminum hydroxide (placebo) applied monthly to grass pollen allergic patients (n = 70). Primary efficacy endpoint was the difference in total nasal symptom score (TNSS) through grass pollen chamber exposure before treatment and 4 weeks after the last injection. Secondary clinical endpoints were total ocular symptom score (TOSS) and allergen-specific skin response evaluated by titrated skin prick testing (SPT) at the same time points. Treatment-related side effects were evaluated as safety endpoints. Changes in allergen-specific antibody, cellular and cytokine responses were measured in patients before and after treatment. Results Sixty-eight patients completed the trial. TNSS significantly decreased with mean changes of − 1.41 (BM32/20 μg) (P = 0.03) and − 1.34 (BM32/40 μg) (P = 0.003) whereas mean changes in the BM32/10 μg and placebo group were not significant. TOSS and SPT reactions showed a dose-dependent decrease. No systemic immediate type side effects were observed. Only few grade 1 systemic late phase reactions occurred in BM32 treated patients. The number of local injection site reactions was similar in actively and placebo-treated patients. BM32 induced highly significant allergen-specific IgG responses (P, Highlights • BM32 is a recombinant allergy vaccine consisting of the preS domain of the large envelope protein of hepatitis B virus (HBV) and grass pollen allergen-derived peptides • Vaccination of allergic patients with BM32 is well tolerated and protects against allergic symptoms induced by grass pollen exposure in a challenge chamber by induction of allergen-specific IgG antibodies without boosting of allergic immune responses • BM32 may be useful as therapeutic and prophylactic vaccine for grass pollen allergy Allergen-specific immunotherapy (AIT) is the only treatment for allergy which prevents the progression of disease to severe manifestations and has long-lasting effects even after discontinuation. However, current forms of AIT based on natural allergen extracts, induce side effects, require multiple administrations, inconvenient up-dosing protocols and thus patients compliance is poor. Our study is the first to investigate the effects of vaccination with a B cell epitope-based recombinant allergy vaccine in patients who were exposed to grass pollen in a pollen chamber. The vaccine contains recombinant fusion proteins consisting of allergen-derived peptides bound to a hepatitis B virus surface antigen as immunological carrier. It is demonstrated that three injections of the recombinant B cell epitope-based allergy vaccine are well tolerated and protect allergic patients against allergic symptoms by induction of allergen-specific IgG antibody responses without inducing allergic sensitization. Thus recombinant hypoallergenic B cell epitope-based vaccines have potential to improve safety and convenience of AIT when used as therapeutic vaccine and, due to low allergenicity, may be used even for prophylactic allergy vaccination.