Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population. Previous studies have identified only a few rare coding mutations. However, recent studies suggest that single nucleotide polymorphisms (SNPs) located near the P2 (beta-cell) promoter of HNF4A are associated with diabetes susceptibility. In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n = 300) and control subjects (n = 310). None of the individual SNPs were associated with type 2 diabetes in this collection of case subjects (P values ranging from 0.06 to 0.99). However, haplotype analysis identifies significant differences between haplotype frequencies in type 2 diabetic case and control subjects (P = 0.013 to P < 0.001), with two uncommon "risk" haplotypes (2.4 and 2.2% of chromosomes) and two uncommon "protective" haplotypes (7.1 and 5.0% of chromosomes) accounting for the evidence of association. Our results suggest that type 2 diabetes linked to 20q12-13 is a heterogeneous disease in which different populations may have different type 2 diabetes susceptibility loci.