Cytokines play a pivotal role in the development of allergies by activating complex signalling mechanisms including the Janus kinase-signal transducer and activator of transcription (JAK- STAT) pathway. Thus, combined activation of a few key transcription factors, one of which is the STAT1 protein, stimulates the expression of a plethora of pro-inflammatory genes. In comparison with common topical steroids we examined the efficacy of a STAT1 decoy oligodeoxynucleotide (dODN) containing ointment on dinitrohalobenzene induced allergic contact dermatitis (ACD) in a guinea pig model. Topical administration of the dODN but not of a mutated control ODN resulted in a profound dose-dependent improvement of both the macroscopic and histolopathological score. Reduced inflammation in STAT1 dODN-treated guinea pig skin was accompanied by a significant decrease in leukocyte infiltration into the dermis and reduced skin thickening. Moreover, STAT1 dODN ointment strongly attenuated expression of interleukins 1b, 8 and 12 as well as that of tumor necrosis factor-a and interferon- [gamma]. When compared to the topical steroids, the STAT1 dODN ointment appeared to be at least as effective. These results potentially demonstrate that topical treatment with a STAT1 dODN has the therapeutic potential for the treatment of allergic and inflammatory skin diseases.