MicroRNAs (miRNAs), a class of non-coding RNAs, bind to the 3' untranslated regions (UTRs) of mRNAs, where they interfere with translation of genes and are implicated in the pathogenesis of diverse diseases. In the present study, we evaluate the impact of rs16917496 polymorphism within the miR-502 miRNA seed region at the 3'UTR of SEDT8 on childhood acute lymphoblastic leukemia (ALL). This case-control study was done on 75 ALL and 115 healthy children. Genotyping of rs16917496 C/T polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that CT as well as CT + TT decreased the risk of ALL in comparison with CC genotype (odds ratio (OR) = 0.29, 95 % confidence intervals (95 % CI) = 0.11-0.78, P = 0.014 and OR = 0.31, 95 % CI = 0.12-0.82, P = 0.016, respectively). Our results demonstrated that SETD8 rs16917496 C/T polymorphism was associated with decreased risk of developing pediatric ALL in Zahedan, southeast Iran. Larger studies with different ethnicities are desired to validate our findings.