ABSTRACT Background Behçet’s disease (BD) is a chronic autoimmune inflammatory disease. Clinical studies revealed that both microRNAs and urotensin II (UTS2) play a significant role in the development of autoinflammatory diseases. Purpose The study aimed to determine the association between miR-146a rs2910164 and UTS2 rs228648 genetic variants and BD susceptibility. In addition, the relationship between these gene variants and clinical and laboratory outcomes among Egyptian patients was investigated. Methods The distributions of miR-146a rs2910164 and UTS2 rs228648 (p.Thr21Met) variants were analyzed in 94 patients with BD and 115 healthy control subjects using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and Taqman Real-time PCR techniques. Results Frequencies of the G/G genotype and G allele of miR-146a rs2910164 variant were significantly higher in patients with BD compared with normal controls (p = .042, OR = 2.31; p = .022, OR = 1.58, respectively). The frequencies of the Thr/Thr genotype and the Thr allele of UTS2 rs228648 variant were significantly higher in subjects with BD compared with normal controls (p = .028, OR = 3.35; p = .032, OR = 1.60, respectively). Conclusion Our results suggest that miR-146a rs2910164 and UTS2 rs228648 variants have significant roles in both the development and clinical modulation of BD in Egyptian patients.