Interleukin-13 (IL13) is believed to play an important role in the pathogenesis of atopy and allergic asthma. To better understand genetic variation at the IL13 locus, we resequenced a 5.1-kb genomic region spanning the entire locus and identified 26 single-nucleotide polymorphisms (SNPs) in 74 individuals from three major populations-Chinese, Caucasian, and African. Our survey suggests exceptionally high and significant geographic structure at the IL13 locus between African and outside Africa populations. This unusual pattern suggests that positive selection that acts in some local populations may have played a role on the IL13 locus. In support of this suggestion, we found a significant excess of high frequency-derived SNPs in the Chinese population and Caucasian population, respectively, as expected after a recent episode of positive selection. Further, the unusual haplotype structure indicates that different scenarios of the action of positive selection on the IL13 locus in different populations may exist. In the Caucasian population, the skewed haplotype distribution dominated by one common haplotype supports the hypothesis of simple directional selection. Whereas, in the Chinese population, the two-round hitchhiking hypothesis may explain the skewed haplotype structure with three dominant ones. These findings may provide insight into the likely relative roles of selection and population history in establishing present-day variation at the IL13 locus, and, motivate further studies of this locus as an important candidate in common diseases association studies.