In comparison to bone marrow, umbilical cord blood has decreased intrinsic immune responsiveness allowing transplantation across HLA barriers with lower rates of graft-versus-host disease. However, laboratory models have also suggested that cord blood may be extremely sensitive to stimulation by cytokines. We report an adult recipient of an ex vivo expanded, HLA-mismatched, unrelated cord blood transplant who experienced a late extramedullary relapse while still in hematologic remission. Despite demonstrating immune tolerance on minimal immunosuppressive agents, a brief course of intravenous interleukin-2 resulted in rapid, aggressive graft-versus-host and graft-versus-leukemia reactions. This case highlights the potential of cytokine immunomodulation following cord blood transplantation, but also suggests caution in stimulating these cells.