Crohn's disease is an idiopathic, relapsing inflammatory disorder of the gastrointestinal tract. We prospectively evaluated the use of extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy, to treat moderate or severe Crohn's disease (Crohn's Disease Activity Index [CDAI] score > or = 220 points) in 2 patients who failed multiple treatments, including immunosuppressants and anti-tumor necrosis factor agents. After at least 24 weeks of ECP with stable concomitant therapy, the patient with moderate disease achieved a clinical response (a decrease in CDAI score from baseline of > or = 100 points and an endpoint CDAI score of < or = 150 points), whereas the other patient with severe disease demonstrated limited improvement. ECP was well tolerated in both patients. These observations suggest that adjunctive ECP can be of benefit among patients with active, refractory Crohn's disease of moderate intensity. Further investigation is needed to define the role of ECP in treating Crohn's disease.