BACKGROUND: Few trials of sublingual immunotherapy (SLIT) in the United States have been reported. OBJECTIVE: This randomized, placebo-controlled feasibility SLIT study compared the safety and physiologic effects of high- versus low-dose Dermatophagoides farinae vaccine. METHODS: Thirty-one D farinae-sensitive adults with allergic rhinitis with or without mild intermittent asthma were eligible for randomization to high-dose maintenance vaccine (n = 10, 4200 allergen units [approximately 70 µg of Der f 1/d]), low-dose maintenance vaccine (n = 10; 60 allergen units [approximately 1 µg of Der f 1/d]), or placebo (n = 11) over 12 to 18 months. Medication-symptom scores and adverse events were monitored, serum D farinae-specific IgE and IgG4 levels were measured, and bronchial reactivity to D farinae was determined at baseline and 6-month intervals. RESULTS: Of the 31 randomized subjects, 6 withdrew because of non-treatment-ascribed events. Four withdrew because of treatment-ascribed effects: high-dose group, 1 of 10 (gastrointestinal symptoms); low-dose group, 1 of 10 (gastrointestinal symptoms); and placebo group, 2 of 11 (headache and increased nasal symptoms). Thus 21 subjects completed the study: high-dose group, 9; low-dose group, 7; and placebo group, 5. Eleven of the 21 subjects experienced mild-to-moderate gastrointestinal symptoms, throat irritation, or both (high-dose group, 5/9; low-dose group, 4/7; and placebo group, 2/5). No severe systemic reactions were noted. No differences in symptom-medication scores were found. High-dose SLIT increased the bronchial threshold to allergen challenge and increased serum D farinae-specific IgG4 levels, whereas low-dose SLIT and placebo had no significant effect. CONCLUSIONS: High-dose D farinae SLIT was generally tolerable, increased serum D farinae-specific IgG4 levels, and improved the bronchial threshold to allergen challenge. Larger US trials are warranted.