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Cytokines and their genes have been described to have an influence on incidence and prognosis in malignant, infectious and autoimmune disease. We previously described the impact of cytokine production on prognosis in paediatric standard-risk acute lymphoblastic leukaemia (ALL).In this study, we investigated the influence of cytokine gene polymorphisms (TNFα, TGFβ, IL10 and IFNγ) on frequency, risk group and prognosis in 95 paediatric ALL-patients. We further report on intracellular production of these cytokines in T-cells.IL10 high-producer-haplotypes were reduced in ALL-patients compared with healthy controls and resulted in a reduced relapse rate compared with low-producer haplotypes. TGFβ high-producer-haplotypes were correlated with a high initial blast-count (codon 25: G/G) and were elevated in high-risk ALL-patients (codon 10: T/T).IL10 was positively and IFNγ-production was negatively correlated with initial blast-count. At diagnosis the expression of TNFα and IFNγ was reduced in patients compared with healthy controls. This was more pronounced in high-risk and in T-ALL-patients.We conclude that gene-polymorphisms of the regulatory/anti-inflammatory cytokines, TGFβ and IL10, but not of the pro-inflammatory cytokines, IFNγ and TNFα, have an impact on prognosis and risk-group of ALL. However, the reduced capacity to produce pro-inflammatory cytokines at diagnosis may serve as another important, functional risk factor. These data may help in further risk stratification and adaptation of therapy-intensity in paediatric patients with ALL. Pediatr Blood Cancer 2015;62:72–79. © 2014 Wiley Periodicals, Inc.