Background: Subcutaneous immunotherapy has emerged as an effective option for treating allergic diseases. Here, we assessed the clinical impact of the mannan-conjugated birch pollen polallergoid T502 in birch pollen-induced allergic rhinoconjunctivitis. Methods: In this prospective, randomized, double-blind placebo-controlled phase III trial, 298 birch pollen–allergic adult patients were treated across 28 trial sites in Germany. Patients received either placebo or 23,000 mTU T502 subcutaneously over five pre-seasonal visits. Efficacy was assessed by comparing the combined symptom and medication score (CSMS) between placebo and T502 during the peak birch pollen season 2022. Safety, tolerability and immunologic effects were also analysed. Results: During the peak birch pollen season, the median CSMS of the T502 group was reduced by 33.00% (p=0.002) compared to placebo. The median daily symptom score and daily medication score were reduced by 30.43% (p<0.001) and 56.25% (p=0.045), respectively. Health related quality of life improved as reflected by reduction of RQLQ values by 31.54% (p<0.0001). Production of Bet v 1 sIgG4 and sIgG increased up to 6.2-fold and 3-fold respectively in the T502 group (p<0.0001). The sIgE/sIgG4 ratio was strongly reduced in the T502 group at V7 (-62.90%, p<0.0001). No fatalities nor serious adverse events were reported. In total, 16 systemic allergic reactions occurred (Grade I/II). Conclusions: Treatment with T502 significantly reduced symptoms and medication need in rhinoconjunctivitis patients. The treatment is well tolerated and safe.