Intensive leukopheresis has been valuable in the short-term palliation of chronic lymphocytic and granulocytic leukemias. A 47-yr-old man with refractory leukemic reticuloendotheliosis (hairy cell leukemia) manifested by anemia, thrombocytopenia, elevated peripheral leukemia cell counts, generalized lymph node enlargement, and leukemic infiltrative skin disease was treated with serial leukopheresis. Removal of approximately 7 X 10(11) peripheral leukemia cells resulted in marked clinical and hematologic improvement with resolution of enlarged lymph nodes and clearing of skin infiltrates. At the time of this reporting, more than 400 wk since the last leukopheresis, the patient continues to do well. The improvement in all blood counts, reduction in lymph node size, and clearing of skin lesions paralleled the reduction of peripheral leukemia cell load by leukopheresis, suggesting mobilization of leukemia cells from marrow, lymph nodes, and skin. Removal of large numbers of leukemia cells in hairy cell leukemia has the potential of achieving sustained clinical improvement and may be a useful alternative therapy for these patients.