Background: Graft-versus-host disease (GVHD) has been associated with non- human leukocyte antigen (HLA) gene polymorphisms after allogenic Hematopoietic stem cell transplantation (aHSCT). Objective: This study aims to investigate the role of three polymorphisms in Nucleotide-binding Oligomerisation Domain (NOD2) gene on the occurrence / severity of acute GVHD among Egyptian population. Methodology: A total of 64 patients and their corresponding donors who underwent aHSCT from HLA-identical matched siblings were genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results were confirmed by automated laser sequencer. Results: There was highly statistical significant association between NOD2 recipient l007fs allele and higher incidence of aGVHD p= 0.006. There was no significant association between NOD2 donor l007fs allele, G908R allele in donors and recipients, R702W in donors and recipients with incidence and severity of aGVHD. Conclusion: This research an original pilot study to demonstrate that the NOD2 SNP13 (Leu1007fs) is a possible risk factor for aGVHD among Egyptian population.