Rationale: 1018 ISS is a synthetic oligonucleotide containing immunostimulatory CpG motifs. In animal studies, 1018 ISS effectively inhibited Th2-mediated lung inflammation, including eosinophil infiltration, and airway hyperresponsiveness. Objectives: To evaluate whether 1018 ISS has activity in subjects with allergic asthma. Methods: Forty subjects (n=21 1018 ISS, n=19 placebo) were enrolled in a randomized double-blind, placebo-controlled, parallel-group study to examine safety, pharmacologic activity, and efficacy of 1018 ISS on allergen-induced airway responses. Subjects received 36 mg of 1018 ISS or placebo by nebulization weekly for four weeks. Measurements: Allergen inhalation challenge was carried out 24h after the 2nd and 4th doses to measure the early and late fall in FEV1. Sputum cells and peripheral blood mononuclear cells were collected pre- and post-dosing, and gene expression was measured by quantitative PCR. Main Results: Treatment with 1018 ISS significantly increased expression of IFN-gamma and IFN-inducible genes, such as IP-10, MIG, ISG-54, MCP-1, and MCP-2 from cells collected post-dose (p<0.05). There was no attenuation of the early or late fall in FEV1 after 1018 ISS compared to placebo, nor a reduction in allergen-induced sputum eosinophils or Th2-related gene expression measured in sputum cells. Conclusions: This study demonstrated that 1018 ISS is safe and pharmacologically active in the respiratory tract of asthmatics but at this dose regimen did not inhibit a fall in FEV1 or other key features of the response to inhaled allergen challenge. This suggests that induction of IFN and IFN-inducible genes alone is not sufficient to inhibit allergen-induced responses in asthmatic subjects.