Osteoarthritis (OA) is a chronic musculoskeletal disorder, characterized by degeneration of articular cartilage and decreased motion range of affected joints. It is regarded as the most common cause of disability among elderly population worldwide. This study aimed to detect interleukin-1 receptor antagonist (IL1RN) genotypes at single nucleotide polymorphism (SNP) rs9005 and rs315943, in patients with knee osteoarthritis, and to clarify their influence on susceptibility and severity of the osteoarthritic disease. Forty-seven unrelated Egyptian patients with primary knee OA and thirty-six control subjects, with matched age, sex and body mass index were included in this study. All patients were subjected to full history taking, general examination and complete knee and joint examination including assessment of the severity of knee OA clinically using the Lequesne'salgofunctional Index and radiological grading by the Kellgren-Lawrence(KL) grade scale. Genotyping assays of IL1RN at SNP rs9005 and rs315943 were performed using real time PCR. IL1RN rs9005 AG, GG genotypes, G allele, as well as rs9005- rs315943 GC haplotype were associated with risk of OA development, while AChaplotype was associated with protective effect against OA development. Younger age of disease onset was associated with rs9005 GG genotype. Higher pain, maximum distance walked, activities of daily living (ADL), Lequesne's scores and KL grading were associated with rs9005 GG, rs315943 CC genotypes and GC haplotype. Whereas, lower pain, maximum distance walked, ADL, Lequesne's scores and KL grading were associated with rs9005 AA, rs315943 TT and AT haplotype.