Background: The mannan-conjugated birch pollen polymerised allergoid EP-088_T502 has previously been shown to reduce allergic symptoms and anti-allergic medication use during the birch pollen season. This confirmatory phase III trial aimed to evaluate the efficacy, safety, tolerability, and immunologic effects of EP-088_T502 administered as eight subcutaneous injections over six pre-seasonal treatment visits. Methods: In this double-blind, placebo-controlled (DBPC) trial, 278 participants with birch pollen–induced allergic rhinoconjunctivitis (ARC) received either placebo or a cumulative dose of 28,000 mannan therapeutic units (mTU) of EP-088_T502. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season. Safety, tolerability, health-related quality of life (QoL), and immunologic parameters were also assessed. Results: In the full analysis set (FAS), EP-088_T502 significantly reduced the CSMS during the peak birch pollen season compared with placebo (mean absolute difference [MAD] −0.31; 95% confidence interval [CI], −0.56 to −0.05; p = 0.0169). In the per-protocol (PP) and complete-case sets, the corresponding MADs were −0.36 (p = 0.012) and −0.51 (p = 0.013), respectively. Health-related QoL improved by 20% in the EP-088_T502 group compared with placebo during the peak season (p < 0.005). EP-088_T502 increased Bet v 1-specific immunoglobulin G4 (IgG4) levels after treatment compared with placebo (6.4-fold; p < 0.0001). The Bet v 1-specific immunoglobulin E (IgE)/IgG4 ratio was reduced by 73% from baseline and by 69% compared with placebo (both p < 0.0001). Thirteen systemic allergic reactions occurred, including one grade III systemic reaction considered related to EP-088_T502. Conclusions: EP-088_T502 significantly improved symptom and medication scores in participants with birch pollen–induced ARC and induced a substantial Bet v 1-specific IgG4 response. The 28,000 mTU regimen induced a substantial immunological response and showed an acceptable safety and tolerability profile.