Behçet disease is a multisystem inflammatory disease with features of vasculitis. It undergoes periods of spontaneous remission and relapse. It often affects the skin, blood vessels, central nervous system, joints, gastrointestinal system, eyes, mucous membrane, and other systems, and it can cause substantial morbidity and mortality. The etiology of Behçet disease remains unknown. Current treatment of Behçet disease involves symptomatic relief with prevention of relapse. We describe the treatment of a recalcitrant case of Behçet disease with infliximab and methotrexate. The patient is a 40-year-old Korean woman with tender lesions on the lower extremities of 1.5 years' duration and intermittent oral and genital ulcerations that failed multiple conventional therapies. The patient was placed on a trial of infliximab. She reported resolution of the tender lower extremity lesions and the oral and vaginal ulcerations shortly after the initiation of the anti-tumor necrosis factor agent. The patient was symptom free for 2 years following the initiation of infliximab. She subsequently reported mild breakthrough oral ulcers and joint pain. The treatment regimen was modified by adding methotrexate 7.5 mg weekly, prednisone 5 mg daily, and a shortened treatment interval of infliximab infusion that resulted in resolution of her symptoms.