We treated 4 patients with refractory International Society of Heart and Lung Transplantation Grades IIIA to IV cardiac allograft rejection with extracorporeal photopheresis. Following treatment on 2 consecutive days, 3 patients demonstrated complete histologic reversal of rejection. The remaining patient improved more gradually, but manifested complete cessation of rejection following three 2-day treatments. We conclude that photopheresis is a safe and effective modality for the treatment of severe refractory cardiac allograft rejection and that these results support the use of photopheresis in this clinical setting.