We describe the case of a patient treated with 2-chloro-2'-deoxyadenosine, CdA or Cladribine for hairy cell leukemia who subsequently developed an Epstein Barr virus (EBV)-positive polymorphous large B-cell lymphoma (p-LBCL). The time interval between Cladribine therapy and development of p-BCL was 11 months and morphologically resembled an EBV-positive post transplant lymphoproliferative disorder (PTLD). Molecular genetic studies for EBV-clonality by Southern blot hybridization showed a clonal population of infected cells, implying that this was an EBV induced lesion. The chronology of events suggest that Cladribine, a purine analog which has been previously described to induce long-lasting immunodeficiency, can, in some cases, weaken the host defense mechanism to a level at which an innocuous EBV infection may transform the normal lymphoid cells into an aggressive neoplasm. Unlike most methotrexate-related lymphoproliferative disorders (LPDs), which undergo spontaneous remission after discontinuation of therapy, LPDs secondary to purine analogs often fails to resolve after discontinuation of therapy and requires additional therapy. Our patient was treated with rituximab following the diagnosis of p-LBCL, with the goal of improving the pancytopenia to permit chemotherapy. However, the patient failed to show any dramatic improvements in counts, developed systemic symptoms and progressive ascites. He expired 3 weeks after a second dose of rituximab. Cladribine is a potent immunosuppressive agent and should be included with the list of immunosuppressive agents that may be associated with EBV-related B-cell lymphoproliferative disorders.