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Background and Aims: Sulfonylureas are the most secondary prescribed oral anti-diabetic drug. Understanding its genetic role in pharmacodynamics can elucidate a considerable knowledge about personalized treatment in type 2 diabetes patients. This study aimed to assess the impact of KCNQ1 variants on sulfonylureas response among type 2 diabetes Iranian patients., Methods and Results: 100 patients were recruited who were under sulfonylureas therapy for six months. 50 responder and 50 non-responder patients were selected. KCNQ1 variants were determined by the RFLP method, and their role in treatment response was assessed retrospectively. Patients with rs2237895 CC and AC genotypes demonstrated a significant decrement in FBS and HbA1c after treatment over patients with AA genotypes (All P < 0.001). Compared to the A allele, the odds ratio for treatment success between carriers with rs2237895 C allele was 4.22-fold (P < 0.001). Patients with rs2237892 CT heterozygous genotype exhibit a higher reduction rate in HbA1c and FBS than CC homozygotes (P=0.064 and P=0.079, respectively). The rs2237892 T allele carriers showed an odds ratio equals to 2.83-fold over C allele carriers in the responder group compared to the non-responder group (p=0.081)., Conclusion: Findings suggest that the KCNQ1 rs2237895 polymorphism is associated with the sulfonylureas response on Iranian type 2 diabetes patients., Competing Interests: Competing InterestWe have no conflict of interest., (© Springer Nature Switzerland AG 2022.)