Pharmacogenomics can explain some of the heterogeneity of sulfonylurea (SU)-related hypoglycemia risk. Recently, a role of OATP1B1, encoded by gene, on SU liver transport prior of metabolism has been uncovered. The aim of the present study was to explore the potential association of c.521T>C polymorphism, leading to reduced OATP1B1 function, with SU-related hypoglycemia risk. Study cohort consists of 176 type 2 diabetes patients treated with the SUs glimepiride or gliclazide. 92 patients reported SU-related hypoglycemia, while 84 patients had never experienced a hypoglycemic event. Patients were previously genotyped for *2 and *3 variant alleles that lead to decreased enzyme activity of the SU metabolizing enzyme CYP2C9 and have been associated with increased SU-related hypoglycemia risk. c.521T>C polymorphism was genotyped by use of PCR-RFLP analysis. c.521TC genotype frequency was significantly lower in hypoglycemic cases than non-hypoglycemic controls (15.2% vs. 32.1%, p=0.008). In an adjusted model, c.521TC genotype significantly reduced the risk of hypoglycemia (OR 0.371; 95% C.I. 0.167-0.822; p=0.015). In CYP2C9 intermediate metabolizers (n=54) c.521TC genotype frequency was significantly decreased in cases compared to controls (3 out of 36 cases, 8.3% vs. 7 out of 18 controls, 38.9%, p=0.012). A similar albeit not significant difference of c.521TC genotype was present in CYP2C9 extensive metabolizers (n=120) (18.2% in cases vs. 30.8% in controls, p=0.113). We have found a protective effect of c.521C variant on SU-related hypoglycemia risk both independently and in interaction with CYP2C9 phenotypes. Our results suggest a possible linkage of c.521T>C polymorphism with variants in other genes impairing OATPs expressed in pancreatic islets that could interfere with SU tissue distribution.