Interleukin (IL)-7, a nonredundant cytokine for B and T cells, plays a central role in cell survival and immune memory formation. Peripheral blood mononuclear cells (PBMCs) from 7 patients after hematopoietic stem cell transplantation (HSCT) diagnosed with posttransplantation lymphoproliferative disease (PTLD) and from 10 Epstein-Barr virus (EBV) polymerase chain reaction-positive HSCT patients (controls) were evaluated for IL-7- and IL-2 induced Stat5 phosphorylation in CD4+ and CD8+ T cells. PBMCs from PTLD+ and control patients exhibited detectable EBV specific CD8+ T cells defined by tetramer analysis. CD4+ and CD8+ T cells from patients with PTLD showed statistically significant reduction in responsiveness to IL-7 compared with PBMCs obtained from controls defined by Stat5 phosphorylation. CD20+ B cells from patients with PTLD and from some EBV+ polymerase chain reaction control individuals exhibited IL-7R expression. Dysregulated immune surveillance, reflected by deficient Stat5 phosphorylation, may facilitate PTLD development despite the presence of EBV-reactive CD8+ T cells. Reduced IL-7 responsiveness will aid to monitor patients after HSCT for increased risk to develop EBV-associated PTLD.