The M-2 protocol was administered every 5 weeks to 25 patients with stage III and IV chronic lymphocytic leukemia (CLL). Complete remission (CR; absence of all clinical and bone marrow evidence of leukemia including normal immune markers for monoclonal disease) and partial remission (PR; greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 X 10(6)/l) were achieved in 20 and 48%, respectively. A median number of 24 cycles of therapy was required to produce a CR. The median duration of unmaintained remission was 12 months. All CR patients are still surviving. The median survival of the PR patients and the overall groups is 21 months. To improve the CR rate and survival in patients with advanced CLL, more effective methods of determining residual leukemic cells and different treatment strategies will be needed.