Type 2 diabetes mellitus (T2DM) is a metabolic pro-inflammatory disorder characterized by chronic hyperglycemia and increased levels of circulating cytokines. Adiponectin, tumor necrosis factor-α (TNF-α), interleukin-6 (Il-6), are important cytokines mediators in the pathogenesis of T2DM. The single nucleotide polymorphisms (SNPs) present in the regulatory regions of cytokine genes often have an impact on their expression levels. Aim: Explore potential associations between SNP+276 G/T of adiponectin, SNP -308 G/A of TNF-α and SNP -174 C/G of IL-6 genes with T2DM and to assess its influence on their serum levels. Subjects and Methods: From the Egyptian population, we enrolled 95 T2DM patients and 85 non-diabetic controls. Serum adiponectin, TNF-α and IL-6 were measured. Genotyping for three SNPs of the adiponectin, TNF-α and IL-6 genes was performed by polymerase chain reaction-restriction fragment length polymorphism. Results: Subjects with the GT/TT genotype of SNP 276 were at increased risk for T2DM (OR=15.88, CI=7.56-33.31, P ≤ 0.01) and associated with hypoadiponectinemia compared with the GG genotype. Furthermore, the allelic frequency of the A allele of SNP 308 was significantly different between T2DM patients compared to controls (X2=30.54, P ≤ 0.0001). Moreover, Individuals with T2DM carrying the GA/AA genotypes had significantly higher serum TNF-α levels than those carrying GG genotype. In addition, Carriers of G allele of IL-6 were significantly more likely associated with T2DM. Conclusion: Genetics variations in Adiponectin +276 G/T, TNF-α 308 G/A and IL-6 -174 C/G may contribute to the disposition for T2DM in Egyptian patients.