The development of a central nervous system (CNS) large cell lymphoma in a patient simultaneously diagnosed with chronic lymphocytic leukemia (CLL) is reported. Although differences in phenotypic expression were demonstrated in study of the peripheral blood and CNS disease, identical immunoglobulin gene rearrangements were identified, providing evidence for evolution of two morphologically distinct neoplasms from the same clone. Beyond histologic transformation, acquisition of an aneuploid cell population in the CNS tumor was demonstrated by analysis of DNA content. Isolated parenchymal involvement of the CNS by large cell transformation of CLL has not been previously described; its relationship to CNS lymphoma and Richter's syndrome are reviewed.