Transcription factor 7-like 2 (TCF7L2) has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups. Regarding the Asian population, Horikoshi et al. (Diabetologia 50:747–751, 2007) and Hayashi et al. (Diabetologia 50:980–984, 2007) reported that single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in the Japanese population, while contradictory results were reported for Han Chinese populations. The aim of this study was to investigate the associations of the TCF7L2 gene with type 2 diabetes using a relatively large sample size: 2,214 Japanese individuals with type 2 diabetes and 1,873 normal controls. The minor alleles of rs7903146, rs11196205, and rs12255372 showed significant associations with type 2 diabetes (OR = 1.48, P = 2.7 × 10⁻⁴; OR = 1.39, P = 4.6 × 10⁻⁴; OR = 1.70, P = 9.8 × 10⁻⁵, respectively) in the combined sample sets. However, neither rs11196218 nor rs290487 showed a significant association. These results indicate that TCF7L2 is an important susceptibility gene for type 2 diabetes in the Japanese population.