A group of 20 patients with stage C chronic lymphocytic leukaemia (CLL) and marked splenomegaly refractory to anti-leukaemia treatment was evaluated in relation to clinical course and survival after splenectomy, and compared with a control group of non-splenectomised CLL patients at the same disease stage. Patients in the former group showed a significant clinical improvement after splenectomy, being reallocated to, and maintained in, stages A (85%) or B (10%) for more than 24 months. Ten patients were still alive 24–135 months after splenectomy. The 10 deaths observed in the group of splenectomised patients occurred 4–69 months after surgery, due to disease progression and/or immunoblastic transformation (4 cases), infectious complications (3 cases) and unrelated causes (3 cases). Analysis of survival from diagnosis showed a significantly better prognosis for patients in the splenectomised group (median survival 10 years, as compared to 3.5 years for the control group). The same statistical difference, p < 0.001, with better life expectancy for splenectomised patients, was observed when the survival was calculated from the time of progression to stage C. These results strongly suggest a beneficial role for splenectomy in advanced CLL with significant splenomegaly, when the accumulation of resistant lymphoid cells precludes an adequate control of the disease by conventional forms of treatment.