BACKGROUND: Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 μg LPP administered subcutaneously over 3 weeks. METHODS: In a randomized, double blind, placebo-controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 μg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) were assessed as secondary endpoints. RESULTS: The mean reduction in CSMS in the LPP vs. placebo group was -15.5% (p=0.041) during the peak period and -17.9% (p= 0.029) over the entire pollen season. LPP treated group had a reduced reactivity to CPT (p<0.001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (p=0.005) compared to placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed ≤ 30 min in 10.5% of LPP-treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication. CONCLUSION: LPP administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms, was generally safe and well-tolerated This article is protected by copyright. All rights reserved.