Allergy to Parietaria causes significant morbidity in most Mediterranean areas. The aim of this study is to investigate the efficacy and tolerance of Parietaria depot extract at 25 BU/mL (1.5 microg/mL Par j 1). We performed a multicenter double-blind, placebo-controlled study in rhinitic patients with/without asthma, sensitized to Parietaria. 42 patients followed 20-month immunotherapy. Clinical efficacy was based on symptom and medication scores and the percentage of healthy days (days without symptoms or medication). Severity of asthma/rhinitis scales, visual analogue scale, evaluation of the treatment by doctors and patients, immediate and delayed cutaneous response and quality of life questionnaires were also studied. The active group showed a sustained decrease in symptoms (p = 0.008), medication (p = 0.009) and both (p = 0.001), and an increase in healthy days (p = 0.001) throughout the study, with a threefold increase of healthy days and almost a three time reduction in medication only after one year of treatment. Asthma and rhinitis severity scales also decreased after immunotherapy, and blinded clinical evaluation by physicians confirmed efficacy in 85% and 77% of the active patients. Patient's self-evaluation returned similar results. None of these changes were observed with placebo. Immediate cutaneous response was significantly reduced at the maintenance phase in the active group and remained reduced throughout the study. Late-phase response after intradermal testing also showed a statistical decrease in actively treated patients. Immunotherapy was well tolerated and every systemic reaction reported was mild. In conclusion, immunotherapy with Parietaria 25 BU/mL is an effective and safe treatment for patients with respiratory allergies.