Methotrexate-associated tumor. A light microscopic and immunohistochemical study. A case of chronic lymphocytic leukemia in a 51-year-old man is described. Within a few months after receiving the immunosuppressive drug, methotrexate, the patient died of acute leukemia. Although initially not suspected, the presence of Reed-Sternberg cells was confirmed by light microscopy and electron microscopy of the lymph node and immunoperoxidase stains for CD3 and UCHL-1. The absence of CD20 in the Reed-Sternberg cells prompted a search for other markers in the malignant cells. By use of monoclonal antibodies and immunoperoxidase techniques, it was determined that the malignant cells in this patient expressed T cell markers (UCHL-1) but were negative for L26 B cell marker and terminal deoxynucleotidyl transferase (TdT). Therefore, based on these results, this lymph node may have represented a methotrexate-associated tumor or lymphoproliferative disorder, not a true mixed cell type. T cell markers (UCHL-1) will be useful for distinguishing drug-induced lymphoma from histologically and phenotypically identical B-cell malignant lymphomas.