The aim of the study was to determine the effectiveness and toxicity of cladribine (2-CdA) used alone or in combination with prednisone (P) or cyclophosphamide and mitoxantrone in re-treatment of patients with progressive B-cell chronic lymphocytic leukemia (B-CLL). We analyzed treatment outcome in 40 patients who had responded to previous treatment with 2-CdA-based regimens. Criteria for re-treatment were the same as for the first treatment. The patients were retreated with the same agents if they responded to the first treatment and then relapsed with progressive disease not earlier than 3 months after achieving the first response. Eight patients received 2-CdA alone (0.12 mg kg(-1) d(-1)) i.v. for 5 d, and 21 patients additionally were given P (30 mg m(-2) d(-1)) orally, also for 5 d. Eleven patients received 2-CdA for 3 d combined with cyclophosphamide (650 mg m(-2)) i.v. and mitoxantrone (10 mg m(-2)) i.v. on day 1 (CMC regimen). The cycles were repeated usually at 4 wk intervals or longer if severe myelosuppression or infections occurred. The therapy was finished if complete remission (CR) was achieved or until maximum of six courses. Overall response (OR) in re-treatment was obtained in 16 out of 40 (40%) patients (95% CI 16-64), including 62% after 2-CdA, 33% after 2-CdA +P and 36% after CMC. CR was obtained in four (10%) patients. Residual disease evaluated in the patients with CR by surface immunophenotyping had been demonstrated in 5 out of 16 (31%) patients after the first treatment and in one out of four (25%) patients after re-treatment. The median progression-free survival (PFS) was 16 months (range 3-39) for the first treatment and 9.5 months (range 3-18) for re-treatment (P=0.34). Grade III or IV neutropenia was observed in 20% patients during the first treatment and in 35% patients during re-treatment (P=0.1). 2-CdA-induced thrombocytopenia occurred in 20% and 42% of the patients, respectively (P=0.05). Anemia was also more frequent during re-treatment (35%) than during the first treatment (7%) (P=0.007). Autoimmune hemolytic anemia developed in four (10%) of the patients during or after re-treatment. Severe infections, including pneumonia and herpes reactivation, occurred in 11 patients during the first treatment and in 10 patients during re-treatment. Twelve (30%) patients died during the study. Infections were the cause of death in six and AIHA in two patients. In conclusion, 2-CdA applied in monotherapy or in combination with prednisone or cyclophosphamide and mitoxantrone has therapeutic activity in some B-CLL patients in whom these drugs induced earlier complete or partial remission. However, since the second response is usually shorter and myelotoxicity more pronounced than during the first therapy, more clinical trials to find other therapeutical approaches are necessary.