Combined treatment of fludarabine (FLU) with cyclophosphamide (CY) may increase the complete remission (CR) rate, decreased minimal residual disease (MRD) and, possibly, prolong survival in B-chronic lymphocytic leukemia patient's (B-CLL). The aim of study was to evaluate the activity and toxicity of FLU in combination with CY, the FLU-CY schedule, in patients with previously untreated B-CLL. From May 1999 to December 2002, 57 patients with advanced or progressive B-CLL received treatment with FLU at a dose of 30 mg/m2 for three consecutive days and CY at a dose of 300 mg/m2 for three days. The cycles were repeated at four week intervals or longer if severe myelosupression occurred. Guidelines for the evalution of response and toxicity were those developed by the National Cancer Institute Sponsored Working Group. Minimal residual disease (MRD) was detected by immunophenotyping only in patients with CR by standard criteria. In the analyzed group an overall response (OR) rate (CR+PR) of 89.5% (95% CI 80.6-94.7%) was achieved, including complete response in 29.8%. At the time of analysis 15 of 17 patients with CR are still in remission. Median duration of follow up in these is 12 (range 4-29.2) months. MRD was detected only in five out of 17(29.4%) patients with CR. Grade III/IV thrombocytopenia was seen in 3 (5.2%) patients and grade III/IV neutropenia in 6 (10.5%). Severe infections were noted in 14 (24%) patients. Two (3.5%) patients died, one due to sepsis, one as a result of disease progression. The FLU-CY regimen is highly effective combination in previously untreated CLL patients with acceptable toxicity. The efficacy of the regimen seems to be higher than that observed earlier after treatment with FLU alone.