Objective To analyze the association of variants of hepatocyte nuclear factor-1α (HNF-1α) gene with type 2 diabetes in Chinese population. Methods In 152 unrelated type 2 diabetes patients and 93 unrelated controls, eleven single nucleotide polymorphisms (SNPs) were identified and genotyped. Statistical analyses were performed to investigate whether these SNPs were associated with diabetes status in our samples. Results In the individual SNP study, no SNP differed significantly in frequency between type 2 diabetes patients and controls. In the haplotype analysis, two haplotype blocks were identified. In haplotype block 1, no evidence was found between common HNF-1α haplotypes and type 2 diabetes. However, in haplotype block 2, a common haplotype GCGC formed by four tagging SNPs (tSNPs) was found to be associated with decreased risk of type 2 diabetes (odds ratio [OR] 0.6011, 95% confidence interval [CI] 0.4138-0.8732,P=0.0073, empirical P=0.0511, permutation test). A similar trend was also observed in the diplotype analysis, indicating that the increasing copy number of the haplotype GCGC was associated with the decreased frequency of diabetes (P=0.0193). Conclusion The results of this study provide evidence that the haplotype of HNF-1α decreases the risk of type 2 diabetes in Chinese individuals.