CD2 is an adhesion molecule present on the cell surface of T and natural killer (NK) cells, and its interaction with CD58 on antigen-presenting cells plays an important role in their immune reaction. Downregulation of CD58 is a frequent mechanism for immune escape in hematological malignancies, whereas there are very few reports that decreased CD2 expression in immune cells is associated with tumor development. We report here a patient who developed Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) along with diminished CD2 expression in T and NK cells. The patient exhibited severely decreased numbers of peripheral T cells and with Th2 cell-biased cytokine production. Although EBV-LPD was refractory to chemotherapy, the patient was treated successfully with allogeneic stem cell transplantation from a donor with normal CD2 expression. It is suggested that CD2-CD58 interactions play a critical role in the anti-tumor immune response, and restoration of this signaling is considered to be an important strategy for anti-tumor therapy when this signaling is blocked.