MiRNAs regulate gene expression by the sequence-specific binding to target mRNA. But the binding affinity may be affected by SNPs residing in miRNA target sites, which may in turn affect the miRNAs’ ability to inhibit the mRNA translation into proteins or lead to degradation of the mRNA. Objective: to investigate the association of the rs16917496 polymorphism within the miR-502 seed region at the 3′ UTR of SETD8 and risk of childhood ALL in a sample of Egyptian population from Kalyobeya Governorate. Method: A case-control study, in which DNA of 40 ALL and 40 healthy children was analyzed for the rs16917496 polymorphism using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Results: SETD8 TT genotype and T allele showed significantly lower frequency in ALL cases when compared to control subjects, with a protective effect against ALL development. Otherwise, no significant association between SETD8 genotypes and alleles and ALL development were observed (OR = 0.125, 95 % CI =0.028- 0.559, P = 0.006 for TT genotype and OR =0.302, 95 % CI =0.154–0.589, P =0.001 for the T allele respectively). Conclusion: SETD8 TT genotype and T allele showed significantly lower frequency in ALL cases when compared to control subjects, with a protective effect against ALL development