Background: Sublingual-swallow immunotherapy was recently recognized in the World Health Organization Position Paper (Allergen immunotherapy: therapeutic vaccines for allergic diseases) “as a viable alternative to parenteral injection therapy to treat allergic diseases” in adults. More controlled studies were required to assess the efficacy and safety of this treatment in children. Objective: This study was carried out to assess the clinical efficacy and safety profile of sublingual-swallow immunotherapy with high-dose allergen in children with allergies. Methods: We used a double-blind placebo-controlled design. Forty-one children with Parietaria -induced rhinoconjunctivitis were randomized to receive sublingual standardized Parietaria judaica extract (n = 20) or placebo (n = 21) for 2 years. The cumulative dose of allergen was 375 times higher than that used in parenteral immunotherapy and the cumulative dose of Par j 1 major allergen was 52.5 mg over 2 years. The main efficacy assessment criteria were symptoms and rescue medication scores recorded on the patients’ diary cards. Secondary criteria were changes in skin and conjunctival specific reactivity as well as blood parameters, analyzed after 1 and 2 years of immunotherapy. The safety of the treatment was assessed by evaluating the frequency and severity of adverse effects. Results: A significant reduction in rhinitis symptoms was observed in the active treatment group during the second season (P = .02), with no difference in medication scores. A significant decrease in skin reactivity (P = .002 after 2 years of treatment) and an increase in the threshold dose for conjunctival allergen provocation test (P = .02) were observed in the active treatment group compared with the group receiving placebo. A significant increase in specific IgG₄ levels (P = .02) was also observed in the active group. Immunotherapy was well tolerated. Conclusion: Sublingual-swallow immunotherapy in Parietaria -allergic children provided a clinical benefit and a decreased specific reactivity to the allergen. The safety profile of this treatment, which constitutes an important issue, indicated good tolerance and compliance. (J Allergy Clin Immunol 1999;104:425-32.)