Patients with relapsed/refractory B-cell chronic lymphocytic leukemia (B-CLL) have a poor treatment outcome. Most patients who are resistant to single agent fludarabine or alemtuzumab (Campath®; anti-CD52 monoclonal antibody) do not survive longer than 9 months; however, combination fludarabine and alemtuzumab (FluCam) appears to have an additive effect in patients who are resistant to either agent alone. This study assessed the efficacy and safety of alemtuzumab at a reduced dose, first in combination with fludarabine and then as monotherapy in patients with relapsed or refractory B-CLL. Patients received fludarabine 25 mg/m2 IV over 30 minutes, and alemtuzumab 10 mg IV over 2 hours for 3 days. Alemtuzumab was titrated for the first 1–3 days and administered with prophylactic antihistamine and antipyretic agents. Acyclovir and cotrimoxazole were used to prevent infection and manage inflammatory complications. Treatment cycles were repeated every 4 weeks for up to 6 cycles, and following successful completion of FluCam, alemtuzumab was administered monthly for 4–5 doses. Response and toxicity were evaluated according to the current criteria of NCI-WG and WHO, respectively. Minimal residual disease (MRD) was assessed with four-color flow cytometry. A total of 10 patients, 33–57 years of age (mean, 48 years), with relapsed or refractory B-CLL received FluCam. Mean time from diagnosis was 6 (range, 2–8) years. Patients had disease classified as Rai stages IV (n=6), III (n=1), II (n=1), and I (n=2). All patients had elevated serum LDH and beta-2 microglobulin, and increased ZAP-70 expression. Patients received a mean of 3 (range, 2-6) prior courses of chemotherapy; 1 patient previously received alemtuzumab, and 6 other patients previously received combination fludarabine and cyclophosphamide. Patients received an average of 4 cycles of FluCam for a total of 37 courses. Following combination FluCam, 3 patients received alemtuzumab on average for 3 (range, 2–5) months. Mean duration of follow-up was 11 (range, 3–27) months. Complete remission was achieved in 2 patients following 3 cycles of FluCam; 1 patient achieved MRD negativity. Short term improvements were seen in 2 patients; however, treatment was discontinued after 2 and 3 cycles because of disease progression. Partial remission was obtained in 6 patients, including total regression of general symptoms and 75% regression of lymphadenopathy and splenomegaly. Moderate side effects including chills, fever, and skin redness were observed in all patients during alemtuzumab dose escalation. Inflammatory complications of grades 2/3 occurred in 1 patient following the first 2 courses of FluCam. One patient with severe immune deficiency died after 27 months of follow up due to bacterial pneumonia. CMV reactivation did not occur in any patient. Results from this study suggest that combination FluCam is active in patients with advanced stages of B-CLL, and may provide a therapeutic option for patients who are refractory to either agent alone. Maintenance therapy with alemtuzumab may prolong time to progression and overall survival without increasing toxicity or hematologic and inflammatory complications in patients with relapsed or refractory B-CLL. Further study is warranted in a larger patient population to confirm these results.