Asthma is a chronic inflammatory disorder of the airways, characterized by wheezing, shortness of breath, chest tightness, and coughing. African Americans are hospitalized for asthma more frequently than the non-Hispanic white population. Most studies suggest a greater incidence of asthma attack in African-Americans than the Caucasian population. The reasons for this disparity are not completely known, however there may be several biological factors involved including variation in genes that are involved in the immunobiology of asthma. ADAM33 and TNFRSF1A genes have been reported to be associated with asthma. ADAM33 is known to function in regulating adhesion and diapedesis of neutrophils through blood vessel epithelial cells from blood to target area. TNFRSF1A is involved in a signaling cascade that leads to the activation of NF-κB which leads to the activation of L-selectin and VCAM-1. The major objective of this study was to investigate the effect of a subset of single nucleotide polymorphisms in ADAM33 and TNFRSF1A genes with asthma. In ADAM33, rs2280091, rs2280090, rs612709 and rs2787094 were selected; while in TNFRSF1A , rs4149623, rs4149637, rs4149570 and rs4149578 were also selected to interrogate their effect with the biology of inflammation in asthma. A case-control study design was used to assess the association of SNPs with asthma. Genotype association analysis showed a significant association of rs2280090, rs2787094 and rs612709 in ADAM33 gene with asthma. When age, gender and body mass index (BMI) were factored in as a co-variant, rs2280090 and rs612709 maintained their significant association with asthma. Haplotype analysis in ADAM33 gene showed significant association with asthma. SNPs in the cytoplasmic domain could effect the deletion of this domain by signal peptidases.