Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy developed for cutaneous T-cell lymphoma, has shown promise in treating chronic graft-versus-host disease (cGvHD) in uncontrolled studies. The purpose of this study was to further examine the effects of ECP on cGvHD. ECP (administered initially 3 times weekly on alternating days) was retrospectively evaluated in 14 patients with extensive cGvHD following allogeneic hematopoietic stem cell transplantation. The median time from transplantation to ECP initiation was 29 months (range, 5-96 months). The median number of concomitant baseline treatments per patient was 3 (range, 0-5). During a median ECP duration of 17 months (range, 3-44 months), 3 patients (21%) achieved a complete cutaneous response (100% improvement), 4 patients (29%) achieved a partial cutaneous response (> or =50% improvement), and 7 patients (50%) had stable skin disease. The median time to response was 6 months (range, 2-15 months), and the median response duration was 5 months (range, 1-31 months). At endpoint, responses were ongoing in 4 patients. Resolution or improvement was noted in arthralgia (5/7 patients), oral changes (3/7), elevated liver enzymes (3/5), dry eyes (2/5), joint stiffness (3/3), pulmonary disease (1/3), and thrombocytopenia (1/1). Because of a favorable response, 11 of 13 patients (85%) who received prednisone at baseline were able to taper (7/13; 54%) or discontinue (4/13; 31%) this medication, and 12 of 14 patients (86%) were able to taper (11/14; 79%) or discontinue (1/14; 7%) ECP. Five-year posttransplantation survival was 77%. Our results suggest that adjunctive ECP improves cutaneous and extracutaneous manifestations of cGvHD and has a steroid-sparing effect.