Beta-defensins are cationic antimicrobial peptides expressed by epithelial cells and exhibit antibacterial, antifungal, and antiviral properties. The defensins are part of the innate host defense network and may have a significant protective role in the oral cavity and other mucosa. Defects or alteration in expression of the beta-defensins may be associated with susceptibility to infection and mucosal disorders. We examined the occurrence of single-nucleotide polymorphisms (SNPs) in the human beta-defensin genes DEFB1 and DEFB2 encoding human beta-defensin-1 and -2 (hBD-1, hBD-2), respectively, in five ethnic populations and defined haplotypes in these populations. Fifteen SNPs were identified in both DEFB1 and DEFB2. Coding region SNPs were found in very low frequency in both genes. One nonsynonymous DEFB1 SNP, G1654A (Val --> Ile), and one nonsynonymous DEFB2 SNP, T2312A (Leu --> His), were identified. Seven sites in each gene exhibited statistically significant differences in frequency between ethnic groups, with the greatest variation in the promoter and in the 5'-untranslated region of DEFB1. DEFB1 displayed 10 common haplotypes, including one cosmopolitan haplotype. Eight common haplotypes were found in DEFB2, including one cosmopolitan haplotype shared among all five ethnic groups. Our results show that genotypic variability among ethnic groups will need to be addressed when performing associative genetic studies of innate defense mechanisms and susceptibility to disease.