Leukocyte infiltration and activation of the CD40-CD40 ligand costimulatory pathway may promote inflammatory processes such as asthma. The aim of this study was to investigate whether a single intratracheal application of a decoy oligodeoxynucleotide (ODN) specific for signal transducer and activator of transcription (STAT) family members 1 and 3 influences leukocyte influx and pulmonary CD40 expression in a rat model of allergic airway inflammation. In comparison with the corticosteroid budesonide, the authors investigated the efficacy of the STAT decoy ODN in ovalbumin-induced allergic asthma in a Brown Norway rat asthma model. Leukocytes of the bronchoalveolar lavage (BAL) and lung tissue were analyzed and expression of CD40 was assessed by Western blotting. Single administration of the STAT decoy ODN but not of a mutated control ODN or budesonide resulted in a significant decrease of eosinophils and T lymphocytes in the BAL fluid. Cell numbers of CD4+ and CD8+ lymphocytes were significantly decreased in the lung tissue after decoy ODN application. CD40 expression in protein extracts from lung tissue was also reduced significantly following STAT decoy ODN treatment. These findings indicate that a single, local application of a transcription factor decoy ODN specific for STAT1 and STAT3 caused an attenuation of the allergen-induced cellular inflammatory reaction and is at least as effective as a topical steroid.