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Interleukin-1 receptor antagonist polymorphism (ILRN) 2 (ILRN*2) has been associated with a poor outcome in septic patients because of an elevated production of anti-inflammatory cytokines. In >70% of patients, morbidity and mortality in childhood acute lymphoblastic leukemia is caused by infections. The aim of this study was to determine the association between this polymorphism and the frequency of septic shock from the time of diagnosis until completion of treatment.This cohort study was conducted in 57 consecutive children with acute lymphoblastic leukemia. At the end of follow-up, children were stratified according to their IL1RN polymorphism (ILRN*1/ILRN*2), evaluating the impact of genotype on the severity of febrile neutropenic events during their treatment.Overall survival was 80% at 55 months after treatment. The average number of febrile neutropenic events in this cohort was 2.82 per patient. Genotype distribution was 50.9% for homozygote IL-1RN*1, 38.6% for heterozygote ILRN*1/ILRN*2 and 10.5% for homozygote IL-1RN*2. The risk of presenting septic shock for homozygote IL1RN*2/IL1RN*2 and heterozygote ILRN*1/ILRN*2 patients was significantly greater (odds ratio, 45; P = 0.001) adjusted for age, gender, risk of leukemia and presence of pathogenic bacteria. Genotype IL-1RN*2 is associated with the risk of development of septic shock in children with acute lymphoblastic leukemia. Further research in larger population-based studies is needed to replicate these findings.This information would allow us to identify more predictive factors in this group of acute lymphoblastic leukemia patients in whom this information is lacking to establish an earlier and more aggressive approach.