The prevalence of diabetes is high and it is associated with high rates of morbidity and mortality. By the year 2030, an estimated 350 million individuals worldwide will suffer from diabetes 1. Type 2 diabetes mellitus (T2DM), which accounts for more than 90 % of diabetes worldwide, is a common, complex, chronic disease with rapidly growing global importance 2. Identifying high-risk groups will likely allow for effective prevention and treatment and is a topic of great interest in diabetic research 3. There are strong evidences that genetic and environmental factors jointly determine its susceptibility 4.T2DM is characterized by insulin resistance and pancreatic B-cell dysfunction 5. The homeostasis model assessment of insulin resistance (HOMA-IR), which is developed for application in large epidemiologic investigations 6, is an alternative to the glucose clamp and the most commonly used surrogate measure of insulin resistance in vivo. Using HOMA-IR makes it possible to study a large number of subjects and with a single glucose and insulin measurement in the fasting state 7. HOMA can be used to assess changes in B-cell function and IR in patients with diabetes to examine the natural history of diabetes and to assess the effects of treatment 8. HOMA can be used to track changes in insulin sensitivity and B-cell function in individuals to indicate whether reduced insulin sensitivity or B-cell failure predominates. The computer model can be used to determine insulin sensitivity (%S) and B-cell function (%B) from paired fasting plasma glucose and insulin data 9.Microsomal epoxide hydrolase (mEPHX, EC 126.96.36.199), is an enzyme involved in the first-pass metabolism of epoxide intermediates, has received particular attention as two functional variants of the gene, which confer slow and fast metabolic activity, have been identified 9. The human mEPHX gene is localized to the long arm of chromosome 1p11 10, and two common aberrant alleles can be detected, which confer slow and fast enzyme activity 9. An exon-3 thymine (T) to cytosine (C) polymorphism changes tyrosine residue 113 to histidine, and enzyme activity is reduced by ?50 % (slow allele). The second mutation, an adenine (A) to guanine (G) transition in exon 4 of the gene, changes histidine residue 139 to arginine, and produces an enzyme with an activity increased by ?25 % (fast allele) 11, 12.While recent evidence suggests that genetic variability in xenobiotic-metabolizing enzymes, such as glutathione S transferases (GSTs), CYP1A1, and CYP2J2, play a role in T2DM development 13, 14, 15, 16, no study has examined the effect of the mEPHX1 exon 3 (Tyr113His) and exon 4 (His139Arg) polymorphisms on risk of T2DM. The purpose of this study was to investigate the effects of mEPHX1 polymorphisms on risk of T2DM based on case–control study and to determine whether mEPHX1 gene polymorphisms synergistically affect insulin resistance.