Background: We investigated the association between genetic variation in chromosomal region 20p13-p12 (ADAM33 and flanking genes ATRN, GFRA4, SIGLEC1 and HSPA12B) and asthma. Amongst asthmatics, we then investigated the association between genetic variants and asthma severity. We evaluated the effect of environmental tobacco smoke (ETS) exposure in the context of genetic variants. Methods: In a case-control study, we recruited 423 asthmatic children and 414 non-asthmatic controls (age 5-18 yr). Amongst asthmatics, we measured lung function and extracted data on hospitalisation for asthma exacerbation from medical records. Early-life ETS exposure was assessed by questionnaire. We included 85 single-nucleotide polymorphisms (SNPs) in the analysis. Results: Seventeen SNPs were significantly associated with asthma; one (rs41534847 in ADAM33) remained significant after correction for multiple testing. Thirty-six SNPs were significantly associated with lung function, of which 15 (six ARTN, three ADAM33, five SIGLEC1 and one HSPA12B) remained significant after correction. We observed a significant interaction between 23 SNPs and early-life ETS exposure in relation to lung function measures. For example, for rs512625 in ADAM33, there was significant interaction with ETS exposure in relation to hospitalisations (pint = 0.02) and lung function (pint = 0.03); G-allele homozygotes had a 9.15-fold [95% CI 2.28-36.89] higher risk of being hospitalized and had significantly poorer lung function if exposed to ETS, with no effect of ETS exposure amongst A-allele carriers. Conclusion: We demonstrated several novel significant interactions between polymorphisms in 20p13-p12 and early-life ETS exposure with asthma presence and, amongst asthmatics, a significant association with the severity of their disease. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.