Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) has been the motive behind a large number of studies in recent years, and previous response, its duration, and development of clonal evolution appear to be the best indicators for the choice of a new regimen. Although alemtuzumab in relapsed/refractory CLL may be beneficial, the optimal dosage and risk of infection related to its use remain thus far deeply controversial issues. In this pilot phase II study we investigated the feasibility of, toxicity of, and response to alemtuzumab at a reduced dose (30 mg s.c. for 2 weeks and then once a week at extended intervals: every 2, 4, 6 weeks up to 1 year). The overall response rate was 95%, with 51% complete response. The complete response range was 55% in fludarabine-relapsed patients and 28% in patients with fludarabine-refractory disease, without significant difference between the two groups. The regimen was well tolerated with mild toxicity and few cytomegalovirus (CMV) infections. With a median follow-up of 27 months, the overall survival (46% at 3 years) appears to be similar to that with other regimens although with fewer adverse events. In conclusion, treatment with alemtuzumab at a reduced dose seems to be safe and increases the event-free survival of patients with relapsed/refractory CLL, compared with the standard dose. A randomized study comparing both regimens including a larger number of patients is warranted.