Background. Asthma is a common polygenic disease, caused by complex interactions between multiple genes and environmental factors. Study of the gene-gene interactions would contribute to a new insight into the pathogenesis and therapeutics of asthma. Objective. To evaluate the single and combined associations of eight single-nucleotide polymorphisms loci in five candidate genes with the development of asthma in Chinese children. Methods. We examined eight single-nucleotide polymorphisms (SNPs) in five key asthma susceptibility genes and performed single SNP association study, haplotype analysis, and gene-gene interactions analysis in 479 Chinese children, including 252 asthmatic subjects and 227 healthy controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Haplotype analysis was detected by SHEsis software. Gene-gene interactions were tested using the multifactor dimensionality reduction (MDR) method. Results. There were significant differences of interleukin (IL)-13 R130Q and IL-13 C1923T in genotype and allele frequency distributions between the asthmatic group and control group. Furthermore, the A allele of IL-13 R130Q and the T allele of IL-13 C1923T were significantly associated with increased risk of asthma (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.20-2.09, p = .0010; OR = 1.57, 95% CI 1.19-2.08, p = .0014, respectively). By haplotype analysis, the C-G and T-A haplotypes consisting of IL-13 C1923T and IL-13 R130Q and the G-A and A-A haplotypes consisting of IL-4R alpha I75V and IL-4R alpha Q576R were significantly associated with asthma (p < .05). Using MDR, the authors detected significant gene-gene interactions with a best six-locus model among IL-4 -C33T, IL-13 R130Q, IL-4R alpha I75V, IL-4R alpha Q576R, STAT6 C2892T, and CD14 -C159T on the risk of asthma (OR = 4.43, 95% CI 1.30-15.04, p < .001, by 1000-fold permutation test). Conclusions. These data suggest that genetic variants in the IL-13 gene may play an important role in the development of pediatric asthma in Middle China. In addition, the significant gene-gene interactions among IL-4 -C33T, IL-13 R130Q, IL-4R alpha I75V, IL-4R alpha Q576R, STAT6 C2892T, and CD14 -C159T may increase an individual's susceptibility to asthma and contribute to the pathogenesis of asthma.</.