Background: The endoribonuclease IRE1 (ERN1) is an important sensor for the endoplasmic reticulum unfolded protein response (UPR), and its activation happens as a result of the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). The ERN1 gene may be involved in ER stress, a feature of type 2 diabetes (T2D). The aim of the study: To investigate the relationship between common single nucleotide polymorphisms (SNPs) of the ERN1 gene and T2D risk. Materials and methods: The study included 1558 T2D patients (586 males and 972 females) and 1611 (618 males and 993 females) healthy subjects. Two common SNPs, such as rs196914 and rs9911085 located in the regulatory region of the ERN1 gene, were genotyped by the MassArray Analyzer-4 system. Results: Genotypes T/C-C/C rs196914 showed an association with an increased risk of T2D (OR=1.18, 95% CI 1.03-1.36, p=0.017). An associative analysis stratified by sex and BMI revealed that this association occurred in females with a BMI greater than 25 kg/m² (OR = 1.20, 95% CI 1.03-1.40, p = 0.02). Furthermore, the genotypes rs9911085 T/C-C/C were linked to T2D risk in females with a BMI greater than 30 kg/m² (OR = 1.44, 95% CI 1.02-1.95, p = 0.034). The haplotype rs196914C-rs9911085C was found to be associated (p=0.004) with T2D risk in overweight and obese subjects (i.e. BMI≥25 kg/m²). Conclusion: The present study was the first to show the impact of ERN1 gene polymorphisms on susceptibility to type 2 diabetes; however, the association was female- and BMI-specific. Further studies are required to confirm the association between ERN1 and T2D risk.