The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131</=P</=0.01377), five with atopic asthma (0.00066</=P</=0.00405) and two with BHR (0.01450</=P</=0.03203) in the Danish population; two SNPs were associated with atopic asthma (0.00397</=P</=0.01481) and four with BHR (0.00435</=P</=0.03544) in the UK population; four SNPs showed associations with asthma (0.00015</=P</=0.03062), two with atopic asthma (0.01269</=P</=0.04042) and three with BHR (0.00259</=P</=0.01401) in the Norwegian population; five SNPs showed associations with asthma (0.00005</=P</=0.03744), five with atopic asthma (0.00001</=P</=0.04491) and three with BHR (0.03568</=P</=0.04778) in the combined population. Three intronic SNPs (rs1420099, rs1362348 and rs1974675) showed replicated association for at least one asthma-related phenotype. These results demonstrate significant association between polymorphisms in IL18R1 and asthma.European Journal of Human Genetics advance online publication, 2 April 2008; doi:10.1038/ejhg.2008.67.