GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II-IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78-94%) and 77% (95% CI, 64-86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II-IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24-0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.