Aim of the work: To study the association of CD226 rs763361 (C>T) and CD40 rs1883832 (C>T) gene polymorphism with the disease susceptibility and activity in Egyptian juvenile idiopathic arthritis (JIA) children. Patients and methods: 150 JIA children and 194 age and sex matched controls were included. CD226 (C>T) polymorphism was assessed using the tetra amplification refractory mutation system-polymerase chain reaction assay (ARMS-PCR) and restriction fragment length polymorphism (RFLP) for CD40 (C>T). The juvenile arthritis disease activity score (JADAS-27) was used to measure the patients’ disease activity. Results: The mean age of the patients was 11.2±1.7years, female: male 4:1 and the disease duration was 4.8±2.3years. 16 were systemic onset, 69 polyarticular and 65 oligoarticular and their mean JADAS-27 was 5.7±5.3. The CD226 TT genotype and T allele were significantly associated with JIA and more frequent than in control (p<0.001). The CD226 T allele was significantly higher in patients with moderate and high activity compared to mild cases (p=0.004 and p<0.001, respectively). The frequency of CD40 C allele was significantly increased in patients with severe and moderate disease activity compared to those with mild (p<0.001 and p=0.02 respectively). Conclusion: There was a genetic association between the CD226 and CD40 gene polymorphism and JIA susceptibility with an impact on disease activity in an Egyptian cohort.