Single nucleotide polymorphisms (SNPs) within nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor (TLR) 5 genes have been recently associated with the incidence and outcome of infections. In this study, we analyzed 38 patients with septic shock after allogeneic stem cell transplantation (allo-SCT) for an association of SNPs within NOD2 and TLR5 genes, with susceptibility to septic shock. One hundred twenty-seven transplant recipients unaffected by any infectious complications were used as controls. We found a significant association between the presence of donor NOD2 SNP13 (3016_3017insC) and the incidence of septic shock (P = .002). In multivariate analysis, donor NOD2 SNP13 appeared as an independent risk factor for the incidence of septic shock after allo-SCT. No association was found for recipient SNPs (NOD2 and TLR5) and donor NOD2 SNP8, SNP12, and TLR5-Stop SNP. Our results suggest that NOD2 SNP13 has an impact on the pathophysiology of severe infectious complications and is an independent risk factor for the development of septic shock after allo-SCT.