Children with asthma and respiratory failure comprise a small but significant subset of children with acute asthma. In addition to clinical and historical factors that have been associated with respiratory failure, there may also be genetic factors that predispose some asthmatic children to intubation and mechanical ventilation. However, this has not previously been assessed in this population. We hypothesized that genetic polymorphisms of the β(2)-adrenergic receptor (ADRβ(2)) are associated with intubation and mechanical ventilation in children with asthma. We performed genotyping of the ADRβ(2) in a pooled cohort of 104 children admitted to the intensive care unit (ICU) with a severe asthma exacerbation between 2002 and 2008. Genotype of the ADRβ(2) was compared with intubation for respiratory failure. At amino acid position 16, 33% (n = 34) of children were homozygous for the glycine allele (Gly16Gly), 15% (n = 16) were homozygous for the arginine allele (Arg16Arg), and 52% (n = 54) were heterozygous (Arg16Gly). At amino acid position 27, 54% (n = 56) of children were homozygous for the glutamine allele (Gln27Gln), 8% (n = 8) were homozygous for the glutamic acid allele (Glu27Glu), and 38% (n = 40) were heterozygous (Gln27Glu). The haplotypes at these positions were Arg16Gly-Gln27Gln (29%, n = 30), Arg16Gly-Gln27Glu (22%, n = 23), Gly16Gly-Gln27Glu (16%, n = 17), Arg16Arg-Gln27Gln (16%, n = 17), Gly16Gly-Gln27Gln (9%, n = 9), and Gly16Gly-Glu27Glu (8%, n = 8). Twelve children in this cohort were intubated for respiratory failure. Intubation was not associated with age, obesity, race/ethnicity, or NHBLI asthma classification. However, children with the Arg16Gly-Gln27Gln haplotype were significantly more likely to be intubated and mechanical ventilated (OR = 4.2; 95% CI = 1.2-14.5; p = .036) than children with other haplotypes of the ADRβ(2). When examining the subset of intubated children, those with the Arg16Gly-Gln27Gln haplotype trended towards longer ICU length of stay (329 ± 270 vs. 124 ± 57 hours; p = .09), but this was not statistically significant. Children with the Arg16Gly-Gln27Gln haplotype of the ADRβ(2) were four times more likely to be intubated and mechanically ventilated during severe asthma exacerbations. Genetic factors may influence the development of a more severe asthma phenotype during acute exacerbations.