Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the and loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the genotype had a significantly increased risk of developing IA ( = 0.00022). We also found that carriers of the allele showed decreased serum levels of TNFSF14 protein ( = 0.0027), and that their macrophages had a decreased fungicidal activity ( = 0.048). In addition, we observed that each copy of the allele increased the risk of IA by 60% ( = 0.0017), whereas each copy of the allele was estimated to decrease the risk of developing the disease ( = 0.0029). Mechanistically, we found that carriers of the risk allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood ( = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin ( = 0.00097). Finally, we also found that carriers of the protective allele had decreased numbers of CD27-IgM-IgD- B cells ( = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells ( = 0.00018 and 0.00023). Altogether, these results suggest a role of the genes in determining IA risk.