IL-4 and IL-13 are important in IgE synthesis and allergic inflammation. Therefore, genes encoding IL-4 and IL-13 are candidates for predisposition to asthma and atopy. A recent study in the YAC transgenic mouse has revealed that one of the conserved noncoding sequences (CNS-1) between IL-4 and IL-13 influences the expression of IL-4, IL-5, and IL-13, suggesting that CNS-1 acts as a coordinate regulator of these genes. This investigation screened for mutations in the 13-kb region between IL-4 and IL-13, which includes the human equivalent of the murine CNS-1. Four single nucleotide polymorphisms (SNPs) were found in the region between IL-4 and IL-13 (IL-4-IL-13SNP1, IL-4-IL-13SNP2, IL-4-IL-13SNP3, and IL-4-IL-13SNP4). There was no mutation in the human CNS-1. We genotyped these and other previously reported polymorphisms in IL-4 and IL-13 using asthmatic families, and examined association by transmission disequilibrium test. Two-locus haplotype analysis revealed that haplotypes composed of the IL-4 RP2del, IL-4 +33T, or IL-4 -589T alleles and either IL-4-IL-13SNP3G or IL-4-IL-13SNP4C are transmitted significantly to asthma-affected children (p = 0.002). This data suggests that haplotypes composed of the 5' region polymorphisms in the IL-4 gene and SNPs in the intergene sequence between IL-4 and IL-13 influence the development of asthma.