Since single drug therapy of chronic lymphocytic leukemia (CLL) has not resulted in prolonged remissions of advanced disease, we initiated a program of combination chemotherapy, COP (cycloposphamide, vincristine sulfate, prednisone) for CLL patients with increasing adenopathy, spenomegaly, and/or signs of marrow failure defined as either anemia or thrombocytopenia. Thirty-six patients received COP either as initial therapy or following progression of disease on single agent therapy. The response rate was 72% with 26 patients responding (16 complete remissions, and 10 good partial remissions). The responses lasted from 8 to 50+ months. Sixteen of the responding patients remain in remission, 2 have active disease and 8 have died. Median survival has not yet been reached but the two-year survival from initiation of COP of the responding patients (complete and good partial response) is 90%. Ten patients had either poor partial or no response with median survival of 18 months. The median survival of the entire group of 36 patients is 35 months. COP is an effective and well tolerated therapy for advanced chronic lymphocytic leukemia.