AbstractThe predominance of severe respiratory syncytial virus (RSV) bronchiolitis in boys compared to girls is well known, but its mechanism is not yet understood. This is the first study focusing on gender‐specific genetic factors affecting the risk of severe RSV infection using a previously described cohort. We determined 347 single‐nucleotide polymorphisms (SNPs) in 470 children hospitalized for RSV infection, their parents, and 1,008 random population controls. We tested if these SNPs exerted a different effect in boys and girls by performing statistical interaction tests. Only one SNP (rs2069885) had a gender‐specific significant association with RSV infection, severe enough to require hospitalization (P‐value 0.00057). The major allele of this structural polymorphism in the interleukin (IL)‐9 gene is associated with an increased susceptibility to severe RSV infection in boys, while there is a decreased susceptibility in girls. Haplotype analysis of two SNPs in the IL‐9 gene (rs2069885 and rs1799962) showed overrepresentation of the TT haplotype in girls with severe RSV bronchiolitis requiring hospitalization indicating that this is the haplotype conferring the highest risk in girls. In conclusion, the IL‐9 genetic polymorphism (rs2069885) has an opposite effect on the risk of severe RSV bronchiolitis in boys and girls. Although so far a difference in IL‐9 production in boys and girls has not been reported, this study may help in explaining the different risks of severe RSV bronchiolitis in boys and girls. Pediatr Pulmonol. 2010; 45:608–613. © 2010 Wiley‐Liss, Inc.