Heterozygous loss-of-function mutations in NEUROD1 have been identified as a very rare cause of maturity-onset diabetes of the young and neonatal diabetes. Previous studies showed that a common A45T variant located in NEUROD1 was inconsistently associated with type 2 diabetes mellitus (T2DM) in different ethnic populations. This study aimed to evaluate the contribution of variant A45T in the genetic pathogenesis of T2DM. A case-control study in a Chinese Han population was conducted, which included 3,554 (1,155 males/2,399 females) patients with T2DM and 4,181 (1,798 males/2,383 females) control subjects from 13 different regions of China. The A45T variant was genotyped by the Illumina GoldenGate platform. A meta-analysis was used to estimate the effects of variant A45T in populations from different ethnic backgrounds. No association in Chinese Han subjects was confirmed in our case control study. A relationship between variant A45T and postprandial glucose was observed in the control group (beta = 0.05, p = 0.002). Meta-analyses did not find an association of this polymorphism with T2DM in Chinese, Japanese, and East Asian descent, but did for European descent Caucasians (odds ratio = 1.15, 95 %CI 1.03-1.28, p = 0.01). Our study suggests the variant A45T does not play a major role in the development of T2DM in East Asian descent, and the role in European descent Caucasian needs to be confirmed.