We have investigated the hypothesis that constitutional genetic variation in IL-5 signalling may be associated with the development or severity of FIP1L1-PDGFRA-positive chronic eosinophilic leukaemia (CEL) in humans. We genotyped six single-nucleotide polymorphisms (SNP) within or close to the IL5RA or IL5 genes in 82 patients with FIP1L1-PDGFRA-positive CEL plus, as controls, healthy individuals (n=100), patients with FIP1L1-PDGFRA-negative eosinophilia (n=100) or patients with chronic myeloid leukaemia (CML) (n=100). We found no association between SNP allele frequency between FIP1L1-PDGFRA-positive and control cases. However, for FIP1L1-PDGFRA cases, we found an association between the genotype at rs4054760, an SNP in the 5'-UTR of IL5RA and peripheral blood eosinophil count (P=0.026) as well as the presence or absence of tissue infiltration (P=0.032). Although these associations fell below the level of significance once corrected for multiple testing, no such association was seen in FIP1L1-PDGFRA-negative cases and no difference in allele frequencies for rs4054760 was seen in control populations across Europe. Furthermore, in an analysis of 112 patients with CML, IL5RA expression was strongly related to rs4054760 genotype (P<0.001). These data suggest that the variations in IL5RA expression are linked to constitutional IL5RA genotype and severity of FIP1L1-PDGFRA disease.