Leukemia treatment strives to eradicate the malignant clone. With T-cell large granular lymphocytic (LGL) leukemia, the onus of treatment appears to be modification of the disease rather than eradication of the clone. We describe a case of T-cell LGL leukemia where aggressive, eradicative type therapy proved ineffective. The patient achieved hematological response to low dose oral methotrexate after failing to respond to and/or tolerate eight previous treatments including CAMPATH-1H and peripheral blood stem cell transplantation. We highlight the resistant nature of the LGL clone and discuss the relative merits of immunomodulatory type therapy in this disease.