cartilage, formation of osteophytes, and eburination of the subchondral bone. Matrilin-3 (MATN-3) is a non-collagenous oligomeric extracellular matrix protein (ECM), which is the smallest member of the matrilin family. This study was conducted to identify the potential association and clinical significance of MATN-3 rs8176070 (SNP6) polymorphism in a series of Egyptian patients with primary knee OA. Material and Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine genotypes of MATN-3 SNP6 for 50 primary knee OA patients in addition to 50 healthy subjects of the same sex and age range. Full history was obtained from OA patients, followed by clinical examination, together with clinical assessment of the severity of knee OA using Lequesne Algofunctional Index score and radiological grading using the Kellgren-Lawrence grade scale (KL). Results: With regard to genotypes of MATN-3 gene SNP6 (rs8176070), a statistically significant difference between OA patients and healthy control subjects was found for the Bb genotype and b allele (p=0.046 and 0.042 respectively), with the prevalence being higher in OA patients with a high risk to develop OA (Odds Ratio [OR]=2.250, 95% CI=1.011-5.008). Patients with the Bb genotype had worse clinical and radiological findings than those with BB and bb genotypes. Conclusion: The investigated polymorphism in the MATN-3 gene may reflect the risk and severity of knee OA in Egyptian patients, particularly with the Bb genotype