Extracorporeal photoimmunotherapy (ECP) has been successfully used as adjunct treatment for steroid-resistant graft-versus-host disease (GvHD) after allogeneic stem cell transplantation. We serially investigated serum levels of soluble interleukin-2 receptor-alpha (sIL-2Ralpha), soluble tumor necrosis factor receptor I (sTNF-RI), and soluble CD8 (sCD8) in 19 patients with steroid-resistant acute GvHD before and after each ECP treatment. Highest levels of sIL-2Ralpha and sTNF-RI correlated with severe acute GvHD and infections. Despite an immediate sIL-2Ralpha and sTNF-RI decrease after each treatment cycle, a mean surge of sTNF-RI>sIL-2Ralpha during the first three ECP cycles was observed in infections. A delayed surge, i.e., after the third ECP cycle, of sIL-2Ralpha and elevated post-ECP sCD8 levels was observed in patients developing chronic GvHD. While levels of sIL-2Ralpha and sTNF-RI correlate with the severity of acute GvHD and infections during the early ECP treatment period, the recurring increase of post-ECP sCD8 possibly may serve as parameter for developing chronic GvHD.