Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice.Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n = 21) or in combination with metformin (n = 135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110.The average duration of diabetes in the study group was 10.6 ± 7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0 ± 0.9). In total, 76 hypoglycemia events were observed (mean 0.48 ± 1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n = 103). Among them, carriers of two wild-type alleles suffered 0.36 ± 0.98 events, while patients with one or two polymorphic alleles had 0.79 ± 1.7 or 2.67 ± 4.6 events, respectively (p = 0.014).Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.