Rationale: The development of atopic diseases is characterized by skewed immune responses to common allergens. Only recently, interferons have been identified to play a crucial role in these mechanisms. Objective: As interferon regulatory factor 1 (IRF-1) is critical for interferon expression we tested the hypotheses that genetic changes in this essential transcription factor may have consequences for the development of atopy. Methods: The IRF-1 gene locus was re-sequenced in 80 human chromosomes. Association and haplotype analyses were performed in a cross-sectional study population of German children from Dresden (n=1,940) and results were replicated in a second population sample from Munich (N=1,159), both part of the International Study of Asthma and Allergy in Childhood (ISAAC phase II). Promoter polymorphism effects were studied using electrophoretic mobility shift assay (EMSA) and colorimetric binding assays. Allele specific IRF-1 gene expression was studied in vitro using luciferase reporter assays while we assessed ex vivo expression of IRF-1 by RT-PCR and INF- protein by Luminex technology. Statistical analyses were performed using SAS/Genetics. Results: By re-sequencing 49 polymorphisms were identified within the IRF-1 gene. Four blocks containing 11 polymorphisms were significantly associated with atopy, total or specific IgE levels in both populations (p<0.05). Two polymorphisms changed transcription factor binding of NF-B and EGR1 to the IRF-1 promoter, altered gene expression in vitro (p=0.0004) and IRF-1 mRNA and IFN- protein expression ex vivo. Conclusion: Our results suggest that functionally relevant IRF-1 polymorphisms influence atopy risk, potentially by altering transcription factor binding, IRF-1 gene expression and IFN- regulation.