Rationale: Genes in the interleukin-4 (IL-4)/IL-13/IL-4R pathway have been shown to be associated with asthma and related phenotypes in some populations, but not in others. Furthermore, interaction between these genes has been shown to affect asthma in Caucasian and Chinese populations. Objectives: To determine whether there are IL-4/IL-13 and IL-4R gene-gene interactions, which are associated with asthma in African Americans. Methods: Eighteen single nucleotide polymorphisms (SNPs) in the IL-4, IL-13, and IL-4R genes were genotyped in 264 African American asthma cases and 176 healthy controls. We tested the SNPs for genetic associations and gene-gene interactions with asthma, baseline lung function, bronchodilator drug response, and total serum IgE levels. Measurements and Main Results: We identified 94 SNPs in the IL-4, IL-13, and IL-4R genes by directly sequencing these genes in 24 African American subjects with asthma. Seventeen SNPs were analyzed for association with asthma and related phenotypes. We found no evidence of association in the IL-4 gene. One SNP in the IL-13 gene (A-646G, rs2069743) and two SNPs in the IL-4R gene (A+4679G, rs1805010 and C+22656T, rs1805015) showed association with lung function (both baseline and post bronchodilator). Although the association between individual SNPs and asthmarelated phenotypes differed from previous studies performed in Caucasian and Chinese populations, significant gene-gene interaction was found between the IL-13 (A-646G) and IL-4R (A+4679G) SNPs for baseline lung function among African American subjects with asthma. Conclusions: Gene-gene interaction between the IL-13 and IL-4R genes may play an important role in asthma among African Americans.