Résumé : Background: Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short-course treatment with adjuvant-free Lolium perenne peptides (LPP) following a 6-week dose-escalation protocol. Methods: In a prospective, dose-escalation study, 61 grass pollen–allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG 4 and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8). Results: No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG 4 levels were higher at V6 (8.1-fold, P <.001) and V8 (12.2-fold, P <.001) than at V1. The sIgE:sIgG 4 ratio decreased at V6 (−54.6%, P <.001) and V8 (−71.6%, P <.001) compared to V1. The absolute decrease in IgE-facilitated allergen binding was 18% (P <.001) at V6 and 25% (P <.001) at V8. Conclusion: Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.