Diabetes mellitus is a worldwide health problem. Type 2 diabetes mellitus constitutes about 90% of all diabetes mellitus cases. Owing to their acceptable efficacy and low cost, metformin and sulfonylureas are usually prescribed together. OCT1 encoded by SLC22A1 gene is responsible for the hepatic uptake of metformin and metformin absorption from the intestine. SNPs of SLC22A1 impact the transporter function, causing inter-patient differences in metformin disposition and efficacy. Metformin is eliminated into the urine via MATE1, which encoded by the SLC47A1 gene, which may impact metformin's responsiveness and side effects. (Kir 6.2) subunits encoded by KCNJ11 may affect the response to sulfonylurea. This study aimed to evaluate the association between SLC22A1 rs72552763 and rs628031, SLC47A1 rs2289669 and KCNJ11 rs5219 genetic variations with sulfonylurea and metformin combination therapy efficacy and safety in Egyptian type 2 diabetes mellitus patients. It was found that KCNJ11 rs5219 heterozygous (EK) and homozygous mutant (KK) genotypes, SLC47A1 rs2289669 heterozygous and homozygous mutant genotypes (AA and GA), and mutant alleles of both polymorphisms were significantly related with increased response to combined therapy. Individuals with the SLC22A1 (rs72552763) GAT/del genotype and the SLC22A1 (rs628031) GA and AA genotypes were at a higher risk for metformin-induced gastrointestinal tract adverse effects.