Background: A member of pattern recognition receptors is the toll-like receptor 4 (TLR-4). It is a highly conserved receptor that can identify compounds like damage- and pathogen-associated molecular patterns. As inflammation is considered to have a very important role in Type 2 diabetes (T2D) and toll-like receptors play a central role in inflammation through immune responses, TLR-4 has a universal role in the T2D mechanism. Excessive amounts of glucose and free fatty acids lead to enlarged expression of TLR-4 mRNA and proteins in cases with T2D. Aim of the study: Is to determine the role of TLR-4 gene polymorphism (rs4986791), threonine 399 isoleucine (Thr399Ile) in the pathogenesis of T2D and diabetic nephropathy (DN) Egyptian patients. Subjects and methods: Sixty patients with T2D, thirty of them with DN and thirty without DN and twenty healthy controls had been genotyped for Thr399Ile polymorphisms of the TLR-4 gene by quantitative real-time PCR. Results: Toll-like receptor 4 polymorphism CT and TT genotypes and T allele found the relationship to T2D (P1). But there had been no significant relationship regarding TLR-4 gene polymorphism among patients with and without nephropathy (P=.674 and .296) for CT and TT genotypes. Conclusion: This study elucidated that the distinguished distribution of genotypes CT and TT of TLR-4 gene polymorphism (rs4986791) among T2D patients and healthy subjects is allied with an increased risk of T2D. But there had been no significant relationship with diabetic nephropathy in Egyptian populations