Multiple meta-analyses in Europeans showed that ENPP1 K121Q polymorphism was associated with type 2 diabetes. However, no association in Japanese, Korean, and Chinese in Taiwan, and inconsistent results in mainland Chinese were reported. In this study, the single nucleotide polymorphism K121Q of the ENPP1gene was genotyped in 539 type 2 diabetes patients and 404 healthy controls. No difference was observed in the genotypic and alle-lic frequencies of ENPP1 K121Q between the cases and the controls. Logistic regression analysis with adjustment of sex, age, and BMI suggested that the XQ genotype was significantly associated with the risk of type 2 diabetes (OR=1.5, 95%CI: 1.39-1.62, P<0.001). Sub-group analysis by gender revealed that the association between ENPP1 K121Q and type 2 diabetes was observed only in women (Q: 12.4% vs. 6.1%, P=0.001; XQ: 23.7% vs. 11.7%, P=0.001). Our results suggest that the association of ENPP1 K121Q with type 2 diabetes in Hubei Han Chinese population is more evident in women. The first meta-analysis of 10 Chinese studies indicated that the Q allele increased the risk of type 2 diabetes (OR=1.42, P=0.042).