Abstract Background The association between genetic polymorphisms of ADRβ2, IL-4, and ADAM3 and asthma remains undetermined. Furthermore, it is not clear as to whether these three gene polymorphisms combined produce a correlative increase in asthmatic risk. Methods A total of 476 asthmatic patients and 115 healthy volunteers were enrolled. Single nucleotide polymorphisms (SNPs) of the C-589T IL-4 promoter (rs2243250), the ADRβ2 gene [at nucleic acid 46 (rs1042713) and 79 (rs1042714)] and the ADAM33 gene [at rs2280091 (T1), rs3918396 (S1), rs3918391 (D1), and rs615436] were analyzed. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE for inhalant allergens and total eosinophil counts were assessed. Results The T allele for the IL-4 gene promoter (C-589T locus), the C allele frequency for ADRβ2 (Gln27Glu locus), and the A allele for the ADAM33 gene (rs2280091, T1) were higher in asthma patients than in normal individuals. In asthmatic patients, the A allele of ADAM33 (rs2280091) was associated with higher eosinophil count and increased hyperresponsiveness compared to the C allele. Combination of the three risk genes SNP had an additive effect on the risk of asthma (OR: 3.46; CI: 1.51–7.93) and increased the diagnostic sensitivity and specificity of asthma. Conclusion Genetic polymorphism in the IL-4 promoter, ADRβ2, and ADAM33 is associated with asthma. Furthermore, ADAM33 genetic polymorphism modifies the phenotype of asthma in atopy and hyperresponsiveness. Asthma is a complex polygenic disease, and combinations of polymorphisms of various genes have an additive effect on the risk of asthma.