Osteoarthritis (OA) is one of the commonest joint disorders that constitute self and social burden because it decreases production and quality of patient’s life. Tumor necrosis Factor-α (TNF-α) displays an essential part in the facilitation of various autoimmune and inflammatory diseases including OA. Gene polymorphism is the main variable that leads to disease origin and progression. This research aimed to clarify the genetic variants of TNF-α and TNF Receptors that are involved in pathogenesis of OA, and to explore the relationship of high TNF-α gene expression and serum level with knee OA in Egyptian patients. This study included 90 idiopathic knee OA patients and 90 healthy individuals as control group. Plasma TNF-α gene expression levels were measured by quantitative real time polymerase chain reaction (qRT-PCR), Genotyping of TNF-α − 308G / A was done by PCRARMS and TNF-α -238G / A by PCR-RFLP. TNFR1 + 36A/G and TNFR2 + 1663A/G were genotyped using TaqMan 5′ -exonuclease allelic discrimination probes. Serum TNF-α level was estimated by ELISA Kit. There was a significant frequency of TNFα-308G/A genotype and A allele in OA patients versus normal individuals. Serums TNF-α level and gene expression were significantly elevated in OA patients as compared to controls. There was no significant relation between TNFα-308, TNFα-238, TNFR1 + 36, TNFR2 + 1663 genetic variants and VAS, WOMAC and Kallegren score, wheras these disability scores were higher frequent in GG genotype than other genotypes of TNFα-308 and TNFα-238. As concluded, TNF-α 308 A allele and G/A genotype act as genetic predisposing factors for increased vulnerability to knee OA in E