Background: Mediterranean fever (MEFV) gene mutations are responsible for familial Mediterranean fever (FMF) and associated with other inflammatory diseases. However, the effects ofMEFVgene mutations on intestinal Behçet’s disease (BD) are unknown. In this study, we investigated these mutations and clinical features in patients with intestinal BD. Methods:MEFVgene analysis was performed in 16 patients with intestinal BD, 10 with BD without intestinal lesions, and 50 healthy controls. Clinical features of patients with intestinal BD were retrospectively assessed. Results: The rates ofMEFVgene mutations in patients with intestinal BD, BD without intestinal lesions, and healthy controls were 75%, 50%, and 38%, respectively. Only 2 of 12 patients with intestinal BD harboringMEFVgene mutations (17%) were controlled without immunosuppressive treatment, while 8 patients (67%) required therapy with tumor necrosis factor (TNF) inhibitors. Among patients with intestinal BD withoutMEFVgene mutations (four patients), three (75%) were controlled by the administration of 5-aminosalicylic acid with or without colchicine, and one (25%) required TNF inhibitors. All patients who underwent intestinal resection hadMEFVgene mutations. Immunohistochemical analysis and in situ hybridization with interleukin-1β (IL-1β) showed a high expression of IL-1β only in injured areas, suggesting that IL-1β may be involved in the formation of ulcers in patients with intestinal BD carryingMEFVgene mutations. Conclusion: Mutations in theMEFVgene may be associated with intestinal lesions of BD and refractoriness to treatment.