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Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. During the course of RSV infection, predominant T helper cell (TH) 2 response is associated with disease progression, whereas predominant TH1 reaction provides convalescence. Interleukin (IL)-18 plays an important role in adjusting the TH1/TH2 immune response to viral infections. Thus, we tested the hypothesis that polymorphisms in IL-18 were associated with severe RSV-associated diseases.We chose to study the promotor polymorphisms −607A/C (rs1946518) and −137G/C (rs187238), the 2 exon polymorphisms 113T/G (rs360718) and 127C/T (rs360717), and 2 intron polymorphisms 5304A/G (rs795467) and 133G/C (rs360721) within the IL-18 gene. Genotyping was performed on 154 children with severe RSV infection as defined by strict clinical criteria and on 270 controls. Statistical analyses of single polymorphisms made use of the Armitage's trend test, haplotypes were calculated with FASTEHPLUS and FAMHAP.−133G/C showed association with severe RSV infection (P = 0.043). The association was further supported by haplotype analyses with all 6 polymorphisms (P < 0.00001 for association with RSV).This study indicates possible involvement of IL-18 in the determination of severe RSV-associated diseases. Defining the genetic basis of RSV bronchiolitis might help us in identifying new drug targets for a more specific therapy. In addition, it might enable an early identification of children at risk for RSV bronchiolitis and thus make a selective prevention feasible.