Background: Fludarabine has been reported to be the most effective single agent in previously treated chronic lymphocytic leukemia (CLL). Based on in vitro synergism of fludarabine with anthracyclines and on results showing a higher efficacy of CHOP against COP it seems to be advisable to try a combination of fludarabine and an anthracycline to improve response rates as well as long-term results. Aim of the multicenter study was to evaluate the rate and duration of remissions and to examine toxicity and immunosuppressive effects of fludarabine and epirubicin in treatment of CLL in stages Binet B and C as first-line therapy or in first relapse. Patients and Methods: 39 patients with CLL in stages Binet B or C or with leukemic immunocytoma were treated with fludarabine 25 mg/m2 day 1-5 and epirubicin 25 mg/m2 day 4+5, for a maximum of 6 cycles every 4 weeks. 39 patients entered the study, out of these 13 patients in first relapse. Results: So far 34 patients are evaluable for response. Overall response rate is 85% with a CR rate of 35%. For the 22 previously untreated patients the response rate is 95% (CR 45%, PR 50%) with only one patient achieving no response. Toxicity: Neutropenia grade 3 occurred in 24 of 122 evaluable cycles, grade 4 in 20 cycles. CD4 lymphocytes decreased in every case with a median of 1356/µl before treatment to 292/µl after cessation of therapy. Infections: 7 herpes zoster and 1 bacterial pneumonia. Other side effects were not observed. 9 patients relapsed to date after 8-23 months of remission. The median remission duration is 15+ months (5-25+ months). The long-term immunosuppressive effect and its consequences are not evaluable so far. Conclusions: The results so far show that the combination of fludarabine and epirubicin is highly effective in the treatment of CLL. Due to the addition of epirubicin to fludarabine it seems to be possible to reach a higher response rate and a more rapid response especially of nodal manifestations. Because of its mild toxicity the presented regimen can be administered in an outpatient facility with the exception of the first cycle. It is effective in untreated patients or in first relapse. To investigate a possible benefit of this presented combination regimen in the treatment of CLL in respect to response and progression-free survival a prospective randomized study comparing fludarabine monotherapy versus combination therapy of fludarabine and epirubicin has been initiated.