Estrogen might play an important role in the pathogenesis of diabetes mellitus type 2. Estrogens inhibit diabetes via distinct mechanisms particularly by reducing both hyperglycemia and plasma insulin levels. Estrogen exerts its physiological effects mainly through estrogen receptors including α and β types. Estrogen receptors are found in many tissues that participate in the pathogenesis of type 2 diabetes. Two common polymorphisms, PvuII and XbaI in estrogen receptor α gene, are reported to be associated with decreased receptor activity and increased risk of diabetes. We aimed to investigate the association between estrogen receptor α polymorphisms and diabetes, where a genetic component may be the major risk factor for this disease. One hundred women with diabetes type 2 were compared with one hundred women without diabetes for PvuII and XbaI polymorphisms. Of whom 61% of cases and 29% of controls had coronary artery disease. The participants were genotyped for these polymorphisms using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. The genotype distribution and frequency of mutated allele showed no significant differences between diabetic and non-diabetic groups in PvuII (χ2=0.981; P=0.612) and XbaI (χ2=0.362; P=0.83) polymorphisms. When coronary artery disease as the potential confounding factor was controlled by logistic regression analysis, it was found that the PvuII and XbaI variants were not related to the type 2 diabetes mellitus (P=0.60 and P=0.99, respectively). Neither PvuII nor XbaI genotypes was associated with increased susceptibility to the type 2 diabetes mellitus in selected Iranian women with diabetes and coronary artery disease.