B-cell chronic lymphocytic leukemia (CLL) initially responds well to treatment with alkylating agents, but subsequently resistance may develop. We recently showed that the nucleoside analogue 2-chlorodeoxyadenosine (CdA) produce a high remission rate in previously treated patients with symptomatic CLL. We report here the results of retreatment with CdA given to 6 previously CdA-treated patients who had progression off therapy. Two initially had a complete remission and 4 a partial remission. The median time from the start of initial CdA-treatment to retreatment was 19 months (range 8-28 mos). The tumor cell response to CdA was assessed by calculating the elimination rate of circulating leukemia cells. The lymphocyte half-life varied in the different patients, but was similar in all six patients when comparing the first CdA-course with CdA-treatment at relapse, with a correlation coefficient of r2 = 0.89. However, the toxicity towards thrombopoiesis was greater at relapse than during the initial treatment in four of the six patients. CLL cells do not seem to acquire resistance to CdA, but retreatment with CdA at relapse following CdA-induced remission is hampered by more severe drug-related cytopenia. Thus, the quality of subsequent reduced, despite continuing sensitivity of the leukemia cells to CdA.