Abstract Background: Behçet’s disease (BD) is a chronic multi-systemic disorder, its exact etiopathology is unknown with both autoimmune and auto-inflammatory mechanisms are suggested. TNFSF15 gene codes for TNF-like ligand 1A (TL1A). TL1A affects the major proinflammatory pathways. Aim: This study aimed to study TNFSF15 (rs3810936) polymorphism distribution, as well as the peripheral blood TNFSF15 expression in BD patients. Methods: This study included 140 healthy controls and 70 BD patients. TNFSF15 gene polymorphism was detected by PCR restriction fragment length polymorphism analysis. The relative expression of TNFSF15 gene was studied by quantitative real-time PCR. Results: BD patients had frequencies of the rs310936 T allele and TT genotype lower than those of the controls (p = 0.037 and 0.033, respectively). TNFSF15 messenger RNA expression in BD patients revealed a significant difference between different genotypes (p<0.001). BD patients with ocular lesion showed a significant decrease in the T allele frequency [OR (95% CI) = 0.1 (0.01-0.68), p= 0.021]. In BD patients with arthritis, there was a significant increase in the T allele frequency of rs3810936 [OR (95% CI) = 4.99 (1.4-17.8), p= 0.013] Conclusions: The commonest genotype of rs3810936 in Egyptian BD patients was C/T. The TT genotype and the T allele frequencies were lower in BD patients than controls. T allele influences the expression of TNFSF15. The rs3810936 is associated with anterior uveitis and arthritis. These findings suggest a possible role for TNFSF15 in the pathophysiology of BD.