Background: Metabolic Syndrome (MetS) mainly comprises hyperglycemia, hypertension and dyslipidemia, and has been proven to increase the risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. Studies have suggested that many factors may be involved in the pathogenesis of MetS, but tumor necrosis factor alpha (TNF- α) may play a strong role as its gene polymorphism was associated with insulin resistance and obesity. The aim of this study was to evaluate the possible association of TNF-α-308 G > A (rs1800629) polymorphism with susceptibility of metabolic syndrome. Methods: a case-control study was conducted upon 128 participants recruited from Suez Canal University Hospital (Ismailia, Egypt), divided into the MetS group (n = 64) and the control group (n = 64). Genotyping of the TNF-α-308 G > A (rs1800629) polymorphism was performed by restriction fragment length polymorphism (PCR-RFLP). Results: The A allele was significantly higher among MetS patients (40%) than controls (11%) (p < 0.0001). A significant association was observed between the healthy and MetS groups under the influence of co-dominant, dominant and overdominant genetic models (p < 0.05). Also, there were positive correlations between TNF-α-308 (G/A) polymorphism and risk factors of metabolic syndrome like body mass index (BMI); fasting blood sugar; cholesterol and low density lipoprotein (LDL) (p < 0.05). Regression analysis was done for predictors of MetS and the A allele was found to be a strong predictor (OR 2.752; 95% CI = 1.106 to 6.847; p = 0.03), as well as, BMI; triglyceride (TG); high density lipoprotein (HDL); LDL and cholesterol (p < 0.05). Conclusions: TNF-α-308 G > A (rs1800629) polymorphism may be play an important role in the development of metabolic syndrome and A allele is a strong predictor in Egyptians.