The IL-12p40 locus has recently been shown to be associated with type 1 diabetes (1). Here, we report the identification of novel microsatellite and single-nucleotide polymorphisms (SNPs) within the IL-12p40 gene and a significant association between a (ATT)n repeat marker and type 1 diabetes in 364 U.S. Caucasian sib-pair families (P < 0.006). Haplotype analysis using the (ATT)n repeat (D5S2941) and the C1159A SNP at the 3' untranslated region of IL-12p40 showed a significant association (P = 0.02). Expression studies in individuals heterozygous for the C1159A SNP indicated that the expression of the 1159A allele is approximately 50% higher than that of the 1159C allele. These results provide genetic and functional evidence for IL-12p40 as a type 1 diabetes susceptibility gene.