Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4 rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4 rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4 rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA. ; Journal Article; This study was supported by grants PI12/02688 from Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III, Madrid, Spain), the ERA-NET PathoGenoMics (03159000A; Ministerio de Ciencia e Innovación PIM2010EPA-00756, Madrid, Spain), the Collaborative Research Center / Transregio 124 FungiNet, the Austrian Science Fundation (FWF I-656-B09), the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo Norte), the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). Agostinho Carvalho and Cristina Cunha were supported by the Fundação para a Ciência e Tecnologia (FCT), Portugal (IF/00735/2014 and SFRH/BPD/96176/2013, respectively).The PCRAGA trial was supported by an unrestricted grant from Pfizer. This study was also supported by Astellas Pharma Inc. and a donation from Consuelo González Moreno, an acute myeloid leukemia survivor.