Acute and chronic graft-versus-host disease (GVHD) continue to be major limitations to successful hematopoietic stem cell transplantation. A variety of different immunosuppressive and immunomodulating modalities have been tested in chronic GVHD, among them extracorporeal photopheresis. Photopheresis is currently indicated and Food and Drug Administration-approved for the treatment of skin manifestations of cutaneous T-cell lymphoma, where the response rate has proved to be considerably high. Extracorporeal photochemotherapy has been evaluated in small cohorts of patients with both acute and chronic GVHD. In steroid-refractory acute GVHD of the skin and liver, the reported response rate is more than 60%, especially in patients with less severe forms of the disease. There is more extensive experience in the treatment of chronic GVHD; overall response rates of 50% and higher have been reported in patients with skin, oral, eye, liver, gastrointestinal, or lung involvement. At our center, we analyzed 63 patients who had 3 or fewer lines of immunosuppressant, including tacrolimus and steroids, to avoid the confounding effects of numerous immunosuppressive therapies. The overall response rate was 59% (n=37), and complete responses were seen in 13 patients. The best responses were observed in GVHD of the skin, liver, oral mucosa, and eye. Our results in chronic GVHD support previous reports of objective responses of skin and visceral GVHD to extracorporeal photopheresis. All of these results indicate activity of extracorporeal photopheresis in acute and chronic GVHD, which warrants further evaluation of this therapy in well-designed, prospective, controlled studies.