In the past decade, a number of case-control studies have been carried out to investigate the relationship between the HHEX polymorphism and type 2 diabetes (T2D). However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the HHEX polymorphism and T2D. In total, 22 association studies on two HHEX polymorphisms (rs1111875 and rs7923837) and risk of T2D published before April 2010, including a total of 36 695 T2D cases and 51 800 controls were included. We also explored potential sources of heterogeneity. In a combined analysis, the summary per-allele odds ratio (OR) for T2D of the rs1111875 and rs7923837 polymorphism was 1.17 [95% confidence interval (CI): 1.13-1.21] and 1.23 (95% CI: 1.18-1.28), respectively. The haplotype analysis also showed significant association in the pooled international populations with an OR of 1.19 (95% CI: 1.15-1.22). In the subgroup analysis by ethnicity, significantly increased risks were found in Asians and Caucasians for these polymorphisms in almost all genetic models. Subgroup analysis also showed that ethnicity is the main source of heterogeneity between pooled studies. This meta-analysis demonstrated that the risk allele of HHEX polymorphisms (rs1111875 and rs7923837) is a risk factor for developing T2D. However, additional very large-scale studies are warranted to provide conclusive evidence on the effects of the HHEX gene on risk of T2D.