Evidence has been obtained showing that endoplasmic reticulum (ER) stress is closely associated with the development of type 2 diabetes (T2D) and that the human X box binding protein 1 (XBP1) is an important transcription factor involved in the development of ER stress. The study aimed to analyze the potential association between polymorphism −116C/G of XBP1 and the risk of T2D. The association between XBP1 polymorphism −116C/G and T2D risk was assessed among 1058 consecutive unrelated subjects, including 523 T2D patients and 535 healthy controls, in a case control study. The −116GG genotype and −116G allele were more frequent in T2D subjects compared with control subjects by statistical analysis, showing that the −116GG homozygote polymorphism of XBP1 might lead to increased susceptibility to T2D in a Chinese Han population. T2D subjects with the −116GG genotype had higher fasting plasma glucose levels, fasting insulin levels, and HbA1c and worse HOMA-IR than the T2D subjects with −116CG and −116CC genotypes (P<0.0001). The study supports a role for −116C/G polymorphism of the XBP1 promoter in the pathogenesis of T2D in a Chinese Han population, and more studies are needed to further evaluate our results.