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The transcription factor nuclear factor erythroid 2-like 2 ( NFE2L2) is essential for preventing type 2 diabetes mellitus (T2 DM)-induced complications in animal models. This case and control study assessed genetic variants of NFE2L2 for associations with T2 DM and its complications in Han Chinese volunteers. T2 DM patients with ( n = 214) or without ( n = 236) complications, or healthy controls ( n = 359), were genotyped for six NFE2L2 single nucleotide polymorphisms ( SNPs: rs2364723, rs13001694, rs10497511, rs1806649, rs1962142 and rs6726395) with TaqMan Pre-Designed SNP Genotyping and Sequence System. Serum levels of heme oxygenase-1 ( HMOX1) were determined through enzyme-linked immunosorbent assay. Informative data were obtained for 341 cases and 266 controls. Between T2 DM patients and controls, the genotypic and allelic frequencies and haplotypes of the SNPs were similar. However, there was a significant difference in genotypic and allelic frequencies of rs2364723, rs10497511, rs1962142 and rs6726395 between T2 DM patients with and without complications, including peripheral neuropathy, nephropathy, retinopathy, foot ulcers and microangiopathy. Furthermore, HMOX1 levels were significantly higher in T2 DM patients with complications than in controls. Multiple logistic regression analysis, however, showed that only rs2364723 significantly reduced levels of serum HMOX1 in T2 DM patients for the GG genotype carriers compared with participants with CG+ CC genotype. The data suggest that although NFE2L2 rs2364723, rs10497511, rs1962142 and rs6726395 were not associated with T2 DM risk, they were significantly associated with complications of T2 DM. In addition, only for rs2364723 higher serum HMOX1 levels were found in the T2 DM patients with CG+ CC than those with GG genotype. [ABSTRACT FROM AUTHOR]