Glibenclamide is a prescribed glucose-lowering medication for diabetes, but there are interindividual variations in the therapeutic response. In this cross-sectional study, the aim was to explore the association of genetic variants in CYP2C9, ABCC8, KCNJ11 and TCF7L2 with good glycaemic control in Mexican type 2 diabetes (T2D) treated with glibenclamide. Patients with T2D receiving treatment with glibenclamide or glibenclamide plus metformin were included. Patients with A1C ≤ 7% were considered to have good glycaemic control, whereas patients with A1C ≥ 8% were considered having poor glycaemic control. Genotyping was performed by real-time PCR using TaqMan probes for the genetic variants. Association was performed by calculating OR with 95% confidence intervals (95% CI). For the multivariate analysis, a multiple logistic regression was performed including the confounding variables age, exercised, BMI, glibenclamide dose, time with T2D and concomitant metformin. Four hundred and four patients were included in the study, median age of the participants was 50 years (IQR 11.0), the median time with disease was 6 years (IQR 8.0), 118 (29.2%) were men, and 243 (60.1%) received glibenclamide in combination with metformin. CYP2C9*3 variant was associated with good glycaemic control (OR = 2.747 [95% CI, 1.194-6.324]), whereas the variants, CYP2C9*2, TCF7L2 rs7903146 and rs12255372, ABCC8 rs757110 and KCNJ11 rs5219, were not. In the multivariate analysis, the CYP2C9*3 variant maintained its association (OR = 2.779 [95% CI, 1.142-6.763]). The findings suggest that CYP2C9*3 genetic variant independently contributes to good glycaemic control of patients with type 2 diabetes treated with glibenclamide. © 2018 John Wiley & Sons Ltd.